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Introduction

The Global Cancer Statistics for 2022 indicate that nearly 20 million new cancer cases are expected in 2022, with 9.7 million cancer-related deaths anticipated in the same year. Cancer remains a leading cause of mortality worldwide (1). Consequently, there is a pressing need to identify novel biomarkers for the early diagnosis and prognosis of cancer and to uncover potential molecular targets for therapy. Research has demonstrated that miRNAs are closely linked to the initiation and progression of cancer and serve as crucial epigenetic regulators in cancer development (2).

MicroRNAs (miRNAs) are small endogenous non-coding RNAs, typically ~22 nucleotides in length, that regulate post-transcriptional gene expression in eukaryotes (3). MiRNAs are initially transcribed as primary miRNAs by RNA polymerase II. These primary miRNAs possess a localized hairpin structure and are cleaved by the Drosha-DGCR8 microprocessor complex subunit complex to form precursor miRNAs. Subsequently, the precursor miRNAs are transported to the cytoplasm, where they are processed by Dicer to generate mature miRNAs. The mature miRNAs bind to Argonaute protein, forming RNA-induced silencing complexes. These complexes generally bind to the 3′-untranslated region (3′-UTR) of target mRNAs, leading to miRNA degradation or the inhibition of protein translation (4,5). As a result, miRNAs regulate various important biological processes, including cell survival, proliferation, autophagy and apoptosis. Dysregulation of miRNAs has been implicated in the development of cancer (6).

Among the numerous miRNAs, miRNA-145-5p has gained significant attention due to its altered expression across a wide variety of cancers. Previous research indicated that miRNA-145-5p levels are lower in prostate cancer cells compared to normal cells, suggesting that its reduced expression may be linked to the development of prostate cancer (7). Furthermore, overexpression of miRNA-145-5p was shown to inhibit epithelial-mesenchymal transition (EMT) and cell proliferation in non-small cell lung cancer (NSCLC), while also enhancing the sensitivity to pemetrexed in NSCLC (8). These results suggest that miRNA-145-5p may be a valuable biomarker and therapeutic target.

The purpose of the present review was to highlight the role of miRNA-145-5p in the progression of different cancers and its effects on chemotherapy and radiotherapy in tumour cells. The review also discusses the systemic delivery approaches for miRNA-145-5p and evaluates its potential as a biomarker for diagnosis, prognosis and treatment response.

Regulation of miRNA-145-5p in cancer

miRNA-145-5p is located on chromosome 5q33.1 and is a member of the miRNA-145 family (9). It is typically transcribed as a double-stranded primary transcript along with miRNA-143. The epigenetic silencing or deletion of this region has been linked to cancer initiation and progression (10). The abnormal expression of miRNAs in cancer is often caused by the regulation of transcription factors and epigenetic alterations, which disrupt the normally controlled cellular RNA network. Several studies have shown that the dysregulation of miRNA-145-5p in cancer is influenced by the following factors:

i) Competing endogenous RNA (ceRNA). Long non-coding RNAs (lncRNA) and circular RNA (circRNA) can act as ceRNAs for miRNA target mRNAs. Both can function as upstream regulators of miRNAs, binding to miRNAs and acting as sponges, which modulate miRNA activity and reduce the suppressive effects of miRNAs on target gene mRNAs. For instance, circRNA carboxypeptidase A4 and lncRNA Hox transcript antisense intergenic RNA have been identified as miRNA-145-5p sponges in cancer, decreasing miRNA-145-5p expression (11,12).

ii) Transcription factors. Heat shock transcription factor-1 (HSF-1) is a transcriptional regulator of miRNA-145-5p and can enhance its inhibitory effect in peritoneal ovarian cancer (13). The c-myb transcription factor binds to the miRNA-145-5p promoter, activating its transcription and increasing miRNA-145-5p expression in esophageal cancer (14).

iii) DNA methylation. DNA methylation occurs at CpG islands within the promoter region. In esophageal squamous cell carcinoma, hypermethylation of the miRNA-145 promoter leads to decreased expression of miRNA-145-5p. Furthermore, increased methylation of the miRNA-145 promoter contributes to the silencing of miRNA-145-5p expression, which facilitates brain metastasis in lung cancer (15). Of note, upstream regulators that enhance the methylation of the miRNA-145 promoter could themselves be downstream targets of miRNA-145 (16). Therefore, targeting these upstream regulators to inhibit their expression and reduce miRNA-145 promoter methylation may restore miRNA-145-5p expression and help prevent disease progression (16).

iv) Other factors. Research has shown that hypoxia triggers the upregulation of miRNA-145-5p expression in glioblastoma, potentially through dependence on hypoxia-inducible factor (HIF)-1 (17).

miRNA-145-5p in different types of cancer

Currently, miRNA-145-5p is known as a tumour suppressor in cholangiocarcinoma, cervical carcinoma, retinoblastoma, renal cell carcinoma (RCC), oral squamous cell carcinoma (OSCC) and osteosarcoma, as well as lung, breast, gastric, pancreatic, ovarian, endometrial, bladder and prostate cancer (18–31). However, in liver, esophageal and colorectal cancer, miRNA-145-5p can act as both a tumour suppressor and an oncogene (14,32–35). Its complexity gives it potential as a therapeutic target. miRNA-145-5p can regulate tumour cell proliferation, apoptosis, metastasis, angiogenesis and other processes by targeting downstream target genes (Fig. 1). However, certain lncRNAs and circRNAs are upstream regulators of miRNA-145-5p, which regulate miRNA-145-5p and downstream target gene expression (Fig. 2). The roles of miRNA-145-5p in different cancers are presented in Table I.

Figure 1. Comprehensive illustration of the interaction between miRNA-145-5p and its major target genes. miRNA, microRNA. TNFAIP2, TNFα-induced protein 2; SOX2, sex determining region Y-box2; ABRACL, ABPA C-terminal like; Sp1, specificity protein 1; NF-κB, nuclear factor kappa-B; SPOP, speckled POZ protein; ARF6, ADP-ribosylation factor 6; SPATS2, spermatogenesis-associated serine-rich 2; KLF5, Krüppel-like factor 5; SERPINE1, serpin family E member 1; Smad3, smad family member 3; CDCA3, cell division cycle-associated protein 3; RHBDD1, rhomboid domain containing 1; FSCN1, fascin actin-bundling protein 1; ARK5, AMPK-related protein kinase 5; Smad4, smad family member 4; c-MYC, myelocytomatosis viral oncogene homolog; EGFR, epidermal growth factor receptor; MUC1, mucin 1; OCT4, octamer-binding transcription factor 4; DUSP6, dual-specificity phosphatase 6; SOX11, SRY-box transcription factor 11; MYO6, myosin VI; TCTP, translationally controlled tumor protein; E2F3, E2F transcription factor 3; S1PR1, sphingosine-1-phosphate receptor 1.

Figure 2. Detailed overview of lncRNAs and circRNAs as upstream regulators interacting with miRNA-145-5p in malignant tumours. miRNA, microRNA; lncRNA, long non-coding RNA; circRNA, circular RNA. circMET, circular RNA mesenchymal epithelial transition factor receptor; CXCL3, C-X-C motif chemokine ligand 3; linc00662, long intergenic RNA 00662; PAFAH1B2, platelet-activating factor acetylhydrolase IB subunit beta; circ_0016760, circRNA 0016760; FGF5, fibroblast growth factor-5; MUC1, mucin 1; lncRNA FOXD2-AS1, lncRNA FOXD2 adjacent opposite strand RNA 1; CDK6, cyclin-dependent kinase 6; lncRNA HOTAIR, lncRNA Hox transcript antisense intergenic RNA; NUAK1, NUAK family kinase 1; KLF5, Krüppel-like factor 5; ST8SIA6-AS1, ST8 α-N-acetyl-neuraminide α-2,8-sialyltransferase 6 antisense 1; MAL2, Mal, T cell differentiation protein 2; circDNM3OS, circRNA DNM3 opposite strand/antisense RNA; MORC2, microrchidia family CW-type zinc finger protein 2; lncRNA NKX2-1-AS1, lncRNA NK2 homeobox 1 antisense RNA 1; SERPINE1, serpin family E member 1; linc-ROR, long intergenic non-protein coding RNA-regulator of reprogramming; POU5F1, octamer-binding transcription factor; lncRNA-TUG1, lncRNA taurine upregulated gene 1; TRPC6, transient receptor potential cation channel subfamily C member 6; IGF2BP1, insulin-like growth factor 2 mRNA-binding protein 1; circSTAG2(16–25), circRNA stromal antigen 2(16–25); TAGLN2, transgelin-2; circ_VANGL1, circular RNA VANGL1; SOX4, sex-determining region Y-related high-mobility group box 4; lnc-ZNF30-3, lncRNA-zinc finger protein 30-3; Twist1, Twist-related protein 1; circPVT1, circRNA plasmacytoma variant translocation 1; TBX15, T-box transcription factor 15; circCEP128, circRNA centrosomal protein 128; lncRNA CASC9, lncRNA cancer susceptibility candidate 9; E2F3, E2F transcription factor 3; circ-ABCB10, circRNA ATP binding cassette subfamily B member 10; lncRNA CBR3-AS1, lncRNA carbonyl reductase 3 antisense RNA 1; GRP78, glucose regulated protein 78 kD.

Table I. Role of miRNA-145-5p in different types of cancer.

Table I.

Role of miRNA-145-5p in different types of cancer.

Type	Upstream regulator	Target	Biological function	Role	(Refs.)
Lung cancer	linc00662	PAFAH1B2	Inhibits cell proliferation and colony formation	Tumour suppressor	(18)
	Hsa_circ_0016760	FGF5	Inhibits cell proliferation, migration and invasion	Tumour suppressor	(36)
	-	TNFAIP2	Inhibits cell migration and invasion	Tumour suppressor	(37)
	circMET	CXCL3	Inhibits cell proliferation, metastasis and immune evasion	Tumour suppressor	(38)
Breast cancer	circ_0009910	MUC1	Inhibits cell proliferation and migration	Tumour suppressor	(19)
	-	SOX2	Inhibits breast cancer progression	Tumour suppressor	(39)
Esophageal cancer	-	ABRACL	Inhibits cell proliferation, migration and invasion	Tumour suppressor	(40)
	-	Sp1 and NF-κB	Inhibits cell migration, invasion and EMT	Tumour suppressor	(32)
		SPOP	Promotes cell proliferation, migration and immune evasion	Oncogene	(14)
	lncRNA FOXD2-AS1	CDK6	Inhibits cell proliferation and invasion	Tumour suppressor	(41)
Liver cancer	LncRNA HOTAIR	NUAK1	Inhibits cell migration, invasion and EMT	Tumour suppressor	(12)
	-	ARF6	Inhibits cell migration, invasion and metastasis	Tumour suppressor	(42)
	-	SPATS2	Inhibits cell proliferation and metastasis	Tumour suppressor	(33)
	LncRNA MEG3	DAB2	Promotes cell metastasis and angiogenesis	Oncogene	(34)
Cholangiocarcinoma	lncRNA ST8SIA6-AS1	MAL2	Inhibits cell growth and migration and promotes apoptosis	Tumour suppressor	(20)
	circDNM3OS	MORC2	Inhibits cell proliferation, migration, invasion and induces apoptosis	Tumour suppressor	(43)
Gastric cancer	-	SERPINE1	Inhibits cell proliferation, migration and invasion	Tumour suppressor	(9)
	-	KLF5	Promotes gastric cancer differentiation	Tumour suppressor	(21)
	linc-ROR	POU5F1 and SOX2	Inhibits cell growth, proliferation and migration	Tumour suppressor	(44)
Pancreatic cancer	-	Smad3	Inhibits tumour growth and promotes apoptosis	Tumour suppressor	(22)
Colorectal cancer	-	-	Inhibits proliferation and invasion of colorectal cancer cells that have not metastasized. Promotes proliferation and invasion of colorectal cancer cells that develop metastasis	Tumour suppressor and oncogene	(35)
	lncRNA-TUG1	TRPC6	Inhibits cell viability, proliferation and migration	Tumour suppressor	(45)
	-	CDCA3	Inhibits cell migration, invasion and EMT	Tumour suppressor	(46)
Cervical carcinoma	-	FSCN1	Inhibits cell migration, invasion and viability	Tumour suppressor	(23)
	-	KLF5	Inhibits cell proliferation, migration and invasion	Tumour suppressor	(47)
Ovarian cancer	-	SMAD4	Inhibits cell proliferation and invasion	Tumour suppressor	(24)
	circ_0015756	PSAT1	Inhibits cell growth, migration and invasion	Tumour suppressor	(48)
Endometrial cancer	-	DUSP6	Inhibits cell proliferation, migration and invasion, and promotes apoptosis	Tumour suppressor	(25)
Bladder cancer	circ_VANGL1	SOX4	Inhibits cell growth and promotes apoptosis	Tumour suppressor	(26)
	-	TAGLN2	Inhibits cell proliferation and migration	Tumour suppressor	(49)
Prostate cancer	lnc-ZNF30-3	Twist1	Inhibits cell metastasis	Tumour suppressor	(27)
Renal cell carcinoma	CircPVT1	TBX15	Inhibits cell growth and metastasis	Tumour suppressor	(28)
Retinoblastoma	lncRNA CASC9	E2F3	Inhibits cell proliferation, invasion and EMT	Tumour suppressor	(29)
Oral squamous cell carcinoma	circ-ABCB10	-	Inhibits cell viability, colony formation and migration	Tumour suppressor	(30)
Osteosarcoma colony formation	-	E2F3	Inhibits cell proliferation and suppressor	Tumour	(31)

[i] LncRNA, long noncoding RNA; circRNA, circular RNA; PAFAH1B2, platelet-activating factor acetylhydrolase IB subunit beta; FGF5, fibroblast growth factor 5; TNFAIP2, TNFα-induced protein 2; CXCL3, C-X-C motif chemokine ligand 3; circMET, circRNA mesenchymal epithelial transition factor receptor; MUC1, mucin 1; SOX2, sex-determining region Y-box 2; ABRACL, ABRA C-terminal like; lncRNA FOXD2-AS1, lncRNA FOXD2 adjacent opposite strand RNA 1; CDK6, cyclin-dependent kinase 6; Sp1, specificity protein 1; NF-κB, nuclear factor κB; EMT, epithelial mesenchymal transition; SPOP, speckled POZ protein; lncRNA HOTAIR, lncRNA Hox transcript antisense intergenic RNA; NUAK1, NUAK family kinase 1; ARF6, ADP-ribosylation factor 6; SPATS2, spermatogenesis-associated serine-rich 2; lncRNA MEG3, lncRNA A maternally expressed gene 3; DAB2, disabled-2; MAL2, Mal, T-cell differentiation protein 2; MORC2, microrchidia family CW-type zinc finger protein 2; KLF5, Krüppel-like factor 5; SERPINE1, serpin family E member 1; linc-ROR, long intergenic non-protein coding RNA-regulator of reprogramming; POU5F1, octamer-binding transcription factor; Smad3, SMAD family member 3; lncRNA-TUG1, lncRNA taurine upregulated gene 1; TRPC6, transient receptor potential cation channel subfamily C member 6; CDCA3, cell division cycle-associated protein 3; SMAD4, SMAD family member 4; PSAT1, phosphoserine aminotransferase 1; DUSP6, dual-specificity phosphatase 6; circ_VANGL1 circRNA van Gogh-like 1; SOX4, sex-determining region Y-related high-mobility group box 4; TAGLN2, transgelin-2; lncRNA CASC9, lncRNA cancer susceptibility candidate 9; E2F3, E2F transcription factor 3; lnc-ZNF30-3, lncRNA-zinc finger protein 30-3; TWIST1, Twist-related protein 1; CircPVT1, circRNA plasmacytoma variant translocation 1; TBX15, T-box transcription factor 15; circ-ABCB10, circRNA ATP binding cassette subfamily B member 10.

miRNA-145-5p as a tumour suppressor

Lung cancer is a common cancer, with ~2.5 million new cases diagnosed worldwide in 2022 (1). Deletion of miRNA-145-5p was found to lead to hyperactivation of HIF-2α, which in turn promotes angiogenesis in lung cancer cells and is associated with poor prognosis (50).

A study reported that miRNA-145-5p negatively regulated TNFα-induced protein 2 levels through combining with its 3′UTR, thus reducing NSCLC cell viability and inhibiting their migration and invasion (37). In addition, circRNA mesenchymal epithelial transition factor receptor (circMET) is associated with poor prognosis of NSCLC. CircMET sponges miRNA-145-5p and promotes the expression of C-X-C motif chemokine ligand 3, a downstream target gene of miRNA-145-5p, which ultimately promotes NSCLC cell proliferation, metastasis and immune evasion (38).

Breast cancer

Breast cancer is a frequent gynecological cancer, with new breast cancer cases in females accounting for 11.6% of all new cancers worldwide in 2022 (1). It has been shown that miRNA-145-5p expression is decreased in both breast cancer cells and tissues. miRNA-145-5p inhibits paclitaxel-resistant breast cancer cell proliferation, migration and invasion, while attenuating paclitaxel resistance by targeting sex-determining region Y-box transcription factor 2 (SOX2) (51).

In addition, circ_0009910 upregulates mucin 1 (MUC1) expression and thus promotes breast cancer proliferation and migration through binding to miRNA-145-5p, while overexpression of miRNA-145-5p reverses this process (19). LncRNA ENST00000422059 also increases Krüppel-like factor 5 (KLF5) protein expression via sponging of miRNA-145-5p, promoting breast cancer cell proliferation and inhibiting apoptosis (52).

Cholangiocarcinoma

Cholangiocarcinoma is a highly heterogeneous malignant tumour of bile duct epithelial cells, prone to metastasis, with an advanced 5-year survival rate of ~5% and a poor prognosis (53). It was found that lncRNA forkhead box D2 adjacent opposite strand RNA 1 [lncRNA ST8SIA6-antisense 1 (AS1)] enhances cholangiocarcinoma cell development and migration, specifically through combining with miRNA-145-5p and upregulating Mal, T-cell differentiation protein 2 expression to promote cholangiocarcinoma progression (20). CircRNA hsa_circ_0005230 (circDNM3OS) and MORC family CW-type zinc finger 2 (MORC2) were upregulated in cholangiocarcinoma tissues, whereas miRNA-145-5p expression was downregulated. CircDNM3OS can act as an miRNA-145-5p sponge to upregulate MORC2 expression, induce cholangiocarcinoma glutamine metabolism, promote cholangiocarcinoma cell proliferation, migration and invasion, and reduce apoptosis, and overexpression of miRNA-145-5p can reverse this process (43).

Gastric cancer

About 783,000 patients with gastric cancer died in 2018. Gastric cancer remains a great challenge that needs to be urgently addressed globally (54). miRNA-145-5p expression decreased within gastric cancer tissues and cells. miRNA-145-5p negatively regulates serpin family E member 1 (SERPINE1) by combining with the 3′-UTR of SERPINE1 and inhibits extracellular signal-regulated kinase-1/2 protein expression, ultimately inhibiting gastric cancer cell proliferation, migration and invasion (9). In addition, miRNA-145-5p expression decreased within undifferentiated gastric cancer compared with differentiated gastric cancer, suggesting that miRNA-145-5p may be associated with the degree of malignancy of gastric cancer. A further study found that miRNA-145-5p also promotes gastric cancer differentiation and reduces gastric cancer by targeting the KLF5-associated degree of malignancy (21). Teng et al (55) found that lncRNA NK2 homeobox-1-AS1 could bind to miRNA-145-5p, promote SERPINE1 expression and activate the vascular endothelial growth factor receptor-2 signalling pathway to promote gastric cancer cell proliferation, metastasis, invasion and angiogenesis.

Pancreatic cancer

Pancreatic cancer is an insidious malignancy and most patients have developed metastases by the time it is detected (56). It was found that miRNA-145-5p expression decreased within pancreatic cancer tissues relative to chronic pancreatitis or normal pancreatic tissues (57). Ding et al (22) found that overexpression of miRNA-145-5p in pancreatic cancer inhibited pancreatic cancer cell proliferation and invasion, and promoted apoptosis, and the regulatory mechanism was related to the inhibition of downstream target gene Smad3 protein expression by miRNA-145-5p. These results highlight that miRNA-145-5p may be utilized as a target in pancreatic cancer.

Cervical carcinoma

Cervical carcinoma is a gynaecological malignancy and according to global cancer statistics, there are 12.4 deaths due to cervical cancer per 100,000 female individuals in certain countries (58). Therefore, there is a need to find new therapeutic strategies. miRNA-145-5p expression decreased within cervical cancer tissues and cells, and miRNA-145-5p overexpression suppressed their migration, invasion and viability by targeting fascin 1, suggesting that miRNA-145-5p is a promising anti-cervical cancer target (23).

Ovarian cancer

Approximately 207,252 deaths worldwide were estimated to be related to ovarian cancer in 2020 (58). miRNA-145-5p expression significantly decreases within ovarian cancer cells vs. healthy ovarian epithelial cells, and miRNA-145-5p upregulation reduces their proliferation while promoting their apoptosis; this result is achieved by miRNA-145-5p by targeting the downstream target gene AMP-activated protein kinase family member 5 (59). Smad4 protein is a signaling protein whose dysfunction is closely associated with cancer (60). miRNA-145-5p prevents ovarian cancer cell proliferation by inhibiting the expression of cell cycle proteins E1, A2 and D1, and inhibits ovarian cancer cell migration by targeting Smad4 (24).

Treatment of peritoneal metastatic ovarian cancer cells using peritoneal heat infusion chemotherapy inhibited ovarian cancer proliferation. The mechanism was associated with significant upregulation miRNA-145-5p expression in ovarian cancer after treatment, thereby inhibiting four downstream target genes, c-MYC, EGFR, MUC1 and octamer-binding transcription factor 4 (OCT4); in addition, HSF-1 acted as a transcriptional regulator in miRNA-145-5p expression and inhibition of HSF-1 impaired the inhibitory effect of miRNA-145-5p on ovarian cancer cells (13).

Endometrial carcinoma

Endometrial cancer is one of the most common gynaecological malignancies in women, which affected ~66,200 female individuals in the US in 2023 (61). It was shown that miRNA-145-5p expression decreased within both cisplatin-resistant endometrial cancer cells and tissues, and circ_0005667 sponged miRNA-145-5p but increased miRNA-145-5p target gene insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) levels, which in turn enhanced the resistance of endometrial cancer cells to cisplatin and promoted cell proliferation, migration and invasion and inhibited apoptosis (62). In addition, miRNA-145-5p inhibits endometrial cancer cell proliferation, migration and invasion, but promotes apoptosis, via targeting dual-specificity phosphatase 6 and silencing its expression (25).

Bladder cancer

Bladder cancer is a highly heterogeneous disease with ~200,000 deaths per year worldwide (58). It has been shown that circRNA hsa_circ_0139697 [circSTAG2 (16–25)] is highly expressed in bladder cancer cells, whereas miRNA-145-5p is lowly expressed; high expression of circSTAG2 (16–25) induces bladder cancer proliferation and invasion, and the specific mechanism is related to circSTAG2 (16–25) sponging miRNA-145-5p, which in turn upregulated transgelin-2 expression (63). In addition, miRNA-145-5p can also be sponged by circRNA van Gogh-like 1, which upregulated sex-determining region Y-related high-mobility group box 4 (SOX4), promoted the viability of bladder cancer cells and reduced bladder cancer sensitivity to adriamycin and apoptosis (26).

Prostate cancer

Prostate cancer serves as a major factor inducing male cancer-associated mortality worldwide, with new cases accounting for 7.3% of all newly diagnosed cancers in 2020 (1). Neuroendocrine prostate cancer is a specific subtype of prostate cancer that is highly malignant, insensitive to endocrine therapy and associated with poor prognosis and tumour progression (64). Low expression of miRNA-145-5p predicts poor differentiation and poor prognosis of prostate cancer; overexpression of miRNA-145-5p suppresses proto-oncogene MYCN expression by targeting SOX11, and then inhibit the neuroendocrine differentiation and cell proliferation of prostate cancer, preventing it from differentiating into prostate neuroendocrine carcinoma (65).

Myosin VI (MYO6) was found to be a protein involved in cytoskeletal motility, which is associated with cancer metastasis and invasion (66). According to Armstrong et al (67), miRNA-145-5p expression decreased within prostate cancer cell lines and MYO6 was the target of miRNA-145-5p, while miRNA-145-5p negatively modulated MYO6 expression and downregulated the expression of waveform protein, fibronectin 1 and actin α2, which in turn inhibited EMT and significantly inhibited the proliferation and migration of prostate cancer cells (67).

RCC

RCC is a cancer originating from the renal tubular epithelium and its most common type is clear cell (cc)RCC (68). CircRNA plasmacytoma variant translocation 1 can act as an miRNA-145-5p sponge and upregulates T-box transcription factor 15 expression, which in turn promotes ccRCC cell growth and metastasis (28). Circ0005875 expression was found to be increased within both ccRCC tissues and cells, and it promoted ccRCC cell proliferation, migration and invasion by sponging miRNA-145-5p, and this may have increased the levels of a target gene of miRNA-145-5p, zinc finger Ebox binding homeobox 2 (69).

Glioma

Glioma is the most frequent primary brain cancer, and accurate and clean removal of the tumour is challenging due to its invasiveness to the surrounding brain tissues (70). According to Zhang et al (71), miRNA-145-5p expression decreased within primary glioma stem cells, and its overexpression suppressed transglial tumour stem cell proliferation while promoting apoptosis, and the mechanism was related to the direct targeting of translationally controlled tumour protein by miRNA-145-5p, downregulating B-cell lymphoma-2 (Bcl-2) expression and upregulating Bcl-2-associated X and cleaved caspase-3. Overexpression of miRNA-145-5p promoted glioma cell sensitivity to temozolomide, which in turn inhibited glioma cell proliferation, the mechanism of which was that overexpression of miRNA-145-5p inhibited the expression of ATP-binding cassette super-family G member 2 (ABCG2) (73). ABCG2 is a drug resistance protein and its decreased expression increases the sensitivity of cancer cells to chemotherapeutic drugs (72); however, circCEP128 can target miRNA-145-5p to reverse the inhibitiory effect of miRNA-145-5p on glioma cells (73).

Retinoblastoma

Retinoblastoma is an intraocular malignant tumour that develops in children, is frequently caused by genetic mutations and is prone to metastasis and invasion (74). miRNA-145-5p expression decreased within retinoblastoma relative to normal retinal tissue, while lncRNA cancer susceptibility candidate 9 (CASC9) expression was significantly increased. lncRNA CASC9 can bind to miRNA-145-5p and then upregulate the expression of E2F transcription factor 3 (E2F3), the miRNA-145-5p target gene of upregulated N-cadherin and Vimentin, and downregulated E-cadherin, and these changes enhanced EMT, thus promoting retinoblastoma cell proliferation and invasion and inhibiting their apoptosis (29).

OSCC

Owing to the prevalence of betel nut and tobacco, OSCC has become a disease that makes it impossible to ignore, and due to its rapid progression, more than half of the patients are found to have metastases (75). miRNA-145-5p expression decreased within OSCC tissues and cells, and circ-ABCB10 was indicated to sponge miRNA-145-5p and inhibit its expression, promoting OSCC cell proliferation and migration (30). circ 0058063 expression was significantly upregulated in OSCC cells. circ0058063 caused SERPINE1 expression to be upregulated by binding to miRNA-145-5p, which in turn promoted migration and proliferation, and facilitated apoptosis of OSCC cells (76).

Thyroid cancer

Thyroid cancer is an endocrine system cancer and papillary thyroid carcinoma (PTC) represents its major subtype, accounting for ~85% of thyroid cancers (77). As discovered by Feng et al (78), lncRNA n384546 expression increased within PTC tissues and cells, which was related to tumour size, lymph node metastasis and poor TNM staging of PTC. Further studies suggested that lncRNA n384546 promoted PTC cell proliferation, invasion and migration. Its mechanism was associated with the lncRNA n384546 sponging and inhibiting the expression of miRNA-145-5p, and upregulation of the expression of AKT serine/threonine kinase 3, an oncogene that is a key protein in several signalling pathways and promotes behaviours such as tumour proliferation, metastasis and drug resistance (79).

Osteosarcoma

Osteosarcoma is a primary bone cancer in children and adolescents, and most osteosarcomas infiltrate surrounding tissues and metastasize; metastasis is a major challenge in the treatment of osteosarcoma (80). miRNA-145-5p could inhibit osteosarcoma proliferation via E2F3 and by suppressing the expression of proteins such as cell cycle protein D1, cyclin-dependent kinase 6 and cell cycle protein E (31). Circ_0008932 sponges miRNA-145-5p and inhibits its expression, promoting the migration and invasion of osteosarcoma (81). Of note, treatment of osteosarcoma Saos-2 cells with allicin down-regulated lncRNA carbonyl reductase 3-AS1 expression, upregulated miRNA-145-5p expression and inhibited target gene glucose regulatory protein 78, causing increased expression of light chain 3-II, Beclin1, CHOP, PERK, eIF2α and CD4+ T cells, which activated endoplasmic reticulum stress, mitochondrial autophagy and immune response, and promoted the apoptosis of osteosarcoma cells (82).

Diffuse large B-cell lymphoma (DLBCL)

DLBCL is the malignant tumour derived from mature B-cells, with ~150,000 new cases each year (83). Gao and Ding (84) found that downregulation of miRNA-145-5p was related to the survival of patients with DLBCL. miRNA-145-5p can directly target sphingosine 1-phosphate receptor 1 (S1PR1), inhibiting the levels of AKT and STAT3 phosphorylation, and thus inhibiting DLBCL cell proliferation, migration and invasion. The miRNA-145-5p/S1PR1 axis brings new perspectives to the treatment of DLBCL (84).

miRNA-145-5p acting as both an oncogene and a tumour suppressor

Esophageal cancer ranks seventh among cancers worldwide; it has a high mortality with an estimated 544,000 esophageal cancer deaths in 2020 (85). Fan et al (40) found that miRNA-145-5p was negatively related to ABRA C-terminal like (ABRACL). miRNA-145-5p inhibited ABRACL expression, which in turn inhibited esophageal cancer cell growth, invasion and migration (40). In addition, miRNA-145-5p targeted nuclear factor κB and specificity protein 1 (Sp1) to inhibit esophageal cancer cell EMT, migration and invasion (32).

Transcription activator C-myb promotes miRNA-145-5p transcription and it subsequently targets speckled POZ protein to upregulate programmed death receptor-ligand 1, while inhibiting T-cell activity, promoting esophageal cancer cell growth and invasion, and thereby inducing immune escape (14). miRNA-145-5p has dual roles in esophageal cancer, possibly due to the different functions of different downstream target genes.

Liver cancer

Hepatocellular carcinoma (HCC) is a cancer with a high mortality rate and it is the most common histological type of liver cancer; statistically, the number of liver cancer deaths accounted for ~7.8% of global tumour deaths in 2022 (1). Wang et al (42) reported that miRNA-145-5p expression decreased within HCC cells and tissues, which was related to poor prognosis and metastatic features of patients with HCC. miRNA-145-5p targeted ADP-ribosylation factor 6 and inhibited HCC cell growth, invasion and migration (42). Furthermore, spermatogenesis-associated serine-rich 2 (SPATS2) expression increased within HCC, which is related to dismal survival and prognosis. miRNA-145-5p directly targets SPATS2 and promotes HCC cell apoptosis and cell cycle arrest in G1 phase (33).

Of note, lncRNA maternally expressed gene 3 could inhibit M2 macrophage polarisation, and consequently HCC cell proliferation, by sponging miRNA-145-5p and upregulating the miRNA-145-5p downstream target gene disabled-2 to influence metastasis and angiogenesis (34). The reason for the dual role of miRNA-145-5p in HCC may be related to the complex network of molecular interactions in cancer cells and the function of targeting different downstream target genes.

Colorectal cancer

Colorectal cancer is a frequent digestive tract cancer. In 2020, epidemiological statistics showed that ~935,000 patients died due to colorectal cancer (58). miRNA-145-5p expression decreased within colorectal cancer cells and tissues, and overexpression of miRNA-145-5p inhibited colorectal cancer cell proliferation, metastasis and EMT, which was associated with miRNA-145-5p inhibiting the expression of a downstream target gene, cell division cycle-associated protein 3 expression (46). Niu et al (86) discovered that miRNA-145-5p downregulation was associated with poor prognosis in colorectal cancer. miRNA-145-5p could target rhomboid domain containing 1 and inhibit the EGFR signalling pathway, which in turn suppressed colorectal cancer cell growth, migration and invasion, but induced cell apoptosis. Cheng et al (35) found that overexpression of miRNA-145-5p in non-metastatic colorectal cancer cells (SW480 cells) suppressed nodal cell growth and their invasive ability, while miRNA-145-5p overexpression in advanced colorectal cancer that had already metastasized (SW620 cells) promoted the proliferation and invasive ability, suggesting the role of miRNA-145-5p as the tumour suppressor of early-stage colorectal cancers without metastasis and as an oncogene in advanced colorectal cancers that have already metastasized (35). The potential mechanisms underlying the dual role of miRNA-145-5p in colorectal cancer may be related to different tumour microenvironments, tumour stages, cell types and genetic backgrounds and this deserves further study.

miRNA-145-5p as a biomarker

Advances in sequencing technologies now allow for the precise and quantitative detection of miRNA-145-5p, underscoring its potential as a biomarker. Numerous studies have confirmed that miRNA-145-5p holds promise as a biomarker for cancer diagnosis, prognosis and prediction of treatment response, providing valuable insights for cancer diagnosis and therapy. A summary of these studies is provided in Table II.

Table II. miRNA-145-5p as a biomarker.

Table II.

miRNA-145-5p as a biomarker.

Type	Direction of deregulated expression	Indication	(Refs.)
Colorectal cancer	Down	Low expression is associated with poor prognosis	(86)
Prostate cancer	Down	Low expression is associated with poor prognosis	(67)
Breast cancer	Down	Low expression is associated with low survival in breast cancer patients	(87)
	Down	Low expression is associated with the achievement of complete pathological remission in breast cancer treated with cisplatin chemotherapy	(88)
Chronic lymphocytic leukemia	Down	Diagnosis of chronic lymphocytic leukaemia	(89)
Glioblastoma	Down	Diagnosis of glioblastoma; low expression implies poor prognosis	(90)
Ovarian cancer	Down	Low expression is associated with poor prognosis and higher staging	(91)

Biomarkers for diagnosis

It was found that miRNA-145-5p expression was significantly reduced in glioblastoma compared to normal tissues, with receiver operating characteristic analysis showing that miRNA-145-5p could potentially be used as a diagnostic marker for glioblastoma, yielding an area under the curve of 0.895 (90). Furthermore, a combination of three miRNAs (miRNA-145-5p, miRNA-218-5p and miRNA-34a-5p) in urine was capable of distinguishing precancerous cervical cancer from healthy individuals as well as patients with cancer (92). By contrast, miRNA-145-5p expression was significantly lower in chronic lymphocytic leukaemia, and its expression levels could differentiate healthy individuals from those with chronic lymphocytic leukaemia (89). In addition, miRNA-145-5p was able to differentiate colorectal tumours from adjacent tissues (93). These findings suggest that miRNA-145-5p has significant potential as a biomarker for cancer diagnosis.

Biomarkers for prognosis

High expression of miRNA-145-5p has been associated with improved patient outcomes in several cancers, including lung cancer (18), prostate cancer (67), breast cancer (87), ovarian cancer (91) and HCC (42). By contrast, low miRNA-145-5p expression may serve as a biomarker for stem cell stemness in breast cancer, which is associated with a worse prognosis in this disease (87). In addition, patients with colorectal cancer with low miRNA-145-5p expression had a death risk 10 times higher than those with high miRNA-145-5p expression levels (94). However, in metastatic colorectal cancer, higher miRNA-145-5p expression was linked to poorer prognosis, suggesting a dual role of miRNA-145-5p in colorectal cancer (35). In summary, miRNA-145-5p is an effective prognostic biomarker, allowing for clinical predictions based on its expression levels in specific cancers.

Biomarkers of therapeutic response

Due to the heterogeneity of cancers, many of which show resistance or no response to treatments, identifying biomarkers of therapeutic response is critical. It was found that miRNA-145-5p expression was significantly reduced in patients with breast cancer who achieved complete pathological remission after treatment with cisplatin or adriamycin compared to those who did not respond to these treatments, suggesting that a decrease in miRNA-145-5p levels after treatment may serve as an indicator of treatment effectiveness (88). Furthermore, a support vector machine model using four miRNAs, including miRNA-145-5p, demonstrated an accuracy of 87.3% in distinguishing responders from non-responders to treatment in esophageal squamous cell carcinoma pathology (95). These findings suggest that miRNA-145-5p could be a valuable biomarker for assessing therapeutic response in certain cancers.

miRNA-145-5p in chemotherapy and radiotherapy

Chemotherapy and radiotherapy are key treatments for cancer. While patients may initially show good responses, cancer cells often develop resistance over time, leading to decreased effectiveness or relapse. Therefore, overcoming drug resistance remains a central issue in cancer research. Recent studies have indicated that miRNA-145-5p is involved in resistance to chemotherapy and radiotherapy in cancer, suggesting that miRNA-145-5p mimics or inhibitors could enhance the efficacy of these treatments. This section explores the role of miRNA-145-5p in platinum-based chemotherapy resistance and its relationship with radiotherapy in cancer (Table III).

Table III. Effect of miRNA-145-5p on chemotherapy.

Table III.

Effect of miRNA-145-5p on chemotherapy.

	Cancer type	Role	Target	(Refs.)
Platinum	Endometrial carcinoma	Increases cisplatin sensitivity	IGF2BP1	(62)
	Ovarian cancer	Promotes cisplatin sensitivity	-	(13)
	Non-small cell lung cancer	Reverses cisplatin resistance	KLF4	(95)
	Colorectal cancer	Promotes oxaliplatin sensitivity	-	(96)
Pemetrexed	Non-small cell lung cancer	Increases pemetrexed sensitivity	Sp1	(8)
Paclitaxel	Breast cancer	Promotes paclitaxel sensitivity	SOX2	(50)
Temozolomide	Glioma	Promotes temozolomide sensitivity	-	(72)
5-Fluorouracil	Gastric cancer	Promotes 5-fluorouracil sensitivity	-	(97)
Sorafenib	Hepatocellular carcinoma	Promotes sorafenib sensitivity	HDAC11	(98)

[i] KLF4, Kruppel-like factor 4; Sp1, specificity protein 1; HDAC11, histone deacetylase 11; IGF2BP1, insulin-like growth factor 2 mRNA-binding protein 1.

Platinum

Platinum-based chemotherapeutic agents, such as cisplatin, oxaliplatin and carboplatin, are widely used in cancer therapy. It has been shown that miRNA-145-5p expression is reduced in both tissues and cells from cisplatin-resistant endometrial cancer. miRNA-145-5p enhances the sensitivity of cisplatin-resistant cells to cisplatin by targeting IGF2BP1, and silencing miRNA-145-5p reverses this effect (62). In addition, increases in miRNA-145-5p levels led to the downregulation of four downstream target genes, c-MYC, EGFR, OCT4 and MUC1, which boosted the sensitivity and anticancer effect of intraperitoneal hyperthermic chemotherapy (cisplatin) in ovarian cancer (13). Similarly, in NSCLC, miRNA-145-5p reversed cisplatin resistance in drug-resistant cells by targeting KLF4 (97). On the other hand, downregulation of miRNA-145-5p expression was associated with increased resistance to oxaliplatin in colorectal cancer cells (97). These findings suggest that boosting miRNA-145-5p expression alongside platinum-based drugs could offer a potential therapeutic approach for cancer treatment.

Other chemotherapy drugs

miRNA-145-5p has been shown to enhance sensitivity to various chemotherapeutic agents. For instance, it increased the sensitivity of glioma to temozolomide (73). SOX2, a protein linked to cancer growth and metastasis, was inhibited by miRNA-145-5p in breast cancer cells, where it reduced resistance to paclitaxel in drug-resistant cells by suppressing SOX2-driven tumour proliferation, migration and invasion (51). In pemetrexed-resistant NSCLC, miRNA-145-5p target Sp1 promoted E-cadherin expression, and reduced snail family transcriptional repressor 1 and zinc finger E-box binding homeobox 1 levels, ultimately reversing resistance to pemetrexed and inhibiting EMT (8). In addition, miRNA-145-5p is known to suppress histone deacetylase 11, enhancing sorafenib sensitivity in HCC (99).

Radiotherapy

Regarding radiotherapy, miRNA-145-5p expression was significantly elevated in patients with colon cancer after 30 radiation treatments, indicating its potential tumour-suppressive role in colon cancer radiotherapy (100). Furthermore, circ_0000392 can bind to miRNA-145-5p to influence the regulator of kinase like protein/MAPK pathway and decrease the sensitivity of cervical cancer cells to radiotherapy (101), suggesting that miRNA-145-5p may inhibit cervical cancer cell resistance to radiotherapy.

Systemic delivery strategies for miRNA-145-5p

Delivering therapeutic miRNAs directly to tumours remains a major challenge in miRNA-based cancer therapies due to their vulnerability to enzymatic degradation. However, exosomal vectors, viral vectors and nanoparticles represent promising methods for effective miRNA delivery (102).

Exosomal vectors

Exosomes are extracellular vesicles, ranging in size from 30 to 100 nm, surrounded by a lipid bilayer, and are crucial for intercellular communication. A study by Ding et al (22) demonstrated that exosomes derived from human umbilical cord mesenchymal stromal cells can deliver miRNA-145-5p into pancreatic ductal carcinoma, leading to a significant increase in miRNA-145-5p expression. This upregulation inhibited pancreatic ductal carcinoma cell proliferation and invasion and promoted apoptosis, suggesting that exosomal delivery of miRNA-145-5p using human umbilical cord mesenchymal stromal cells could be a promising therapeutic approach for pancreatic ductal carcinoma (22).

Viral vectors

Currently, viral vectors frequently used for delivering miRNAs include adeno-associated viruses, lentiviruses and adenoviruses (103). Sun et al (104) developed a lentiviral vector modified with liposome to create a liposome-lentivirus hybrid, which efficiently delivered miRNA-145-5p to liver cancer stem cells, resulting in its overexpression. This overexpression inhibited the Wnt/β-catenin signaling pathway, thereby suppressing self-renewal, migration and invasion of liver cancer stem cells by targeting collagen type IV alpha 3 chain (104). This experiment showed that using liposome-lentiviral hybrid vectors to deliver miRNA-145-5p is a viable method. However, the immunogenic potential and risk of mutations with viral vectors have prompted the search for safer and more effective alternatives.

Nanoparticle vectors

Nanoparticle drug delivery systems are composed of nanoscale particles, typically ranging from 1 to 1,000 nm, made from pharmaceutical materials and drugs. These systems have advantages such as targeted delivery, controlled release, efficient cellular uptake and enhanced drug stability (105).

A poly-l-lysine functionalized melanin nanoparticle (MNP-PLL)/miRNA-145-5p system was developed (106), which successfully transfected miRNA-145-5p into laryngeal squamous cell carcinoma cells, leading to a significant increase in miRNA-145-5p expression. It was further demonstrated that combining the MNP-PLL/miRNA-145-5p system with photothermal therapy effectively inhibited the migration of laryngeal squamous cell carcinoma cells, offering a novel strategy for combining gene-targeted therapy with photothermal treatment in cancer (106).

Dai et al (107) created a modular peptide probe nanoparticle that efficiently delivered miRNA-145-5p into ovarian cancer cells, increasing miRNA-145-5p levels and inducing apoptosis in the cancer cells.

Ultrasound-targeted microbubble destruction (UTMD) is a non-invasive method that enhances drug delivery to cells and tissues, improving the efficiency of nanoparticle delivery systems (108). Ren et al (109) applied UTMD to significantly boost miRNA-145-5p delivery to breast cancer cells, increasing its expression. This upregulation of miRNA-145-5p bound to and inhibited actin gamma 1 expression, resulting in reduced growth, migration and invasion of breast cancer cells (109).

Although current research indicates that systemic delivery methods for miRNA-145-5p effectively target tumour cells and enhance their expression, several challenges still exist with these delivery systems. One major issue is the need to balance maintaining efficient delivery with managing potential toxicity from the vectors themselves or due to overdosing. For instance, viral vectors, which integrate into the host genome, can trigger immune responses, both innate and adaptive, resulting in cytotoxic damage. In addition, cationic nanoparticles have been shown to provoke immune reactions and excessive cationic components can cause the nanocarriers to break down at the glomerular basement membrane, leading to the clearance of miRNA by the kidneys (110). Another concern is off-target effects, as miRNAs can influence multiple genes simultaneously, leading to unintended regulatory effects. Furthermore, when viral vectors integrate into or near undesirable genomic regions, they may disrupt gene expression and activate proto-oncogenes, potentially contributing to the development of other cancers (111). As such, further research is necessary to address these issues and minimize systemic adverse reactions.

Controversies

This study provides an overview of miRNA-145-5p's role in various cancers, evaluating its potential as a biomarker, its effect on radiotherapy and chemotherapy, and its systemic delivery strategies, all of which may assist in cancer diagnosis and treatment. However, as an miRNA, miRNA-145-5p is influenced by environmental factors and it appears to have a dual role as both a tumour suppressor and an oncogene in cancers such as esophageal, colorectal, and liver cancer. This duality may be due to miRNAs targeting distinct downstream genes, which can lead to conflicting findings in research. Therefore, it is crucial to investigate the relationship between miRNA-145-5p and its multiple downstream target genes across different cancer types.

Furthermore, there are certain inconsistencies in the reported expression levels of miRNA-145-5p. For instance, variable results have been reported regarding its expression in esophageal cancer cells and tissues (14,40), as well as in plasma, serum and tissues of patients with breast cancer (51,112,113). These discrepancies are not easily explained by a single mechanism but may involve several factors. First, specific cancers may selectively release certain miRNAs, and miRNAs in circulating fluids could show higher levels in serum or plasma, while their expression in tissues or cells may be reduced (114). In addition, miRNAs may be secreted into the extracellular space and incorporated into extracellular vesicles, such as exosomes, to avoid degradation by circulating fluids, leading to higher expression levels (115). Variations in the tumour microenvironment could also contribute to differences in miRNA expression in both cells and circulation (116). These conflicting results may stem from differences in cancer cell lines, sample sizes, study populations and cancer stages, and additional research is needed to better understand these variations.

Conclusions

This review assessed the roles of miRNA-145-5p in various cancer types. It was found that miRNA-145-5p generally acts as a tumour suppressor in most cancers, although it demonstrates a dual role in liver, esophageal and colorectal cancers. Mechanistically, miRNA-145-5p can directly target its downstream genes or be regulated by upstream factors, such as lncRNAs and circRNAs, thereby influencing cancer development. In addition, miRNA-145-5p has potential as a biomarker for cancer diagnosis, prognosis and treatment response. It can also impact the sensitivity to chemotherapy and radiotherapy, and the use of miRNA-145-5p mimics or inhibitors could potentially overcome drug resistance in certain cancers. Finally, systemic delivery methods for miRNA-145-5p are promising for advancing effective miRNA-based therapies targeting tumours. Together, these findings provide comprehensive evidence that could inform future strategies for cancer treatment and drug development.

Acknowledgements

Not applicable.

Funding

Funding: No funding was received.

Availability of data and materials

Not applicable.

Authors' contributions

ZC performed the literature search, wrote major parts of the manuscript, edited the manuscript and prepared the figures and tables. YQ conceptualized the study and oversaw the process. Data authentication is not applicable. Both authors have read and approved the final version of the manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

All authors declare that they have no competing interests.

References