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Introduction

Hepatitis B virus X (HBX) protein has a long peptide chain composed of 154 amino acids. The N-terminus of HBX is the negative regulatory domain and the C-terminus is the deactivation domain (1). In 1998, a protein that interacts with the C-terminus of HBX was first identified and named HBX-interacting protein (IP), also known as Lamtor5. HBXIP is encoded by four exons located on human chromosome 1p13.3, and is a conserved protein with a molecular weight of 18 kDa. HBXIP localizes subcellularly to the surface of lysosomes and forms a pentameric regulatory complex with the other four proteins of the Lamtor family to activate mammalian target of rapamycin complex (mTORC1) (2,3). mTORC1 is the major growth regulator in humans and serves a role in cell growth (4,5).

HBXIP is highly expressed in numerous types of cancer, such as breast cancer, gastric cancer and esophageal squamous cell carcinoma, and its expression is associated with certain clinicopathological characteristics (6–14). Furthermore, high levels of HBXIP expression are associated with a poor prognosis.

Research on HBXIP has revealed multiple carcinogenic mechanisms. For example, in cervical cancer, HBXIP can interact with LIM domain 2 and activate the Wnt signaling pathway to promote malignant progression (15). In ovarian cancer, HBXIP can coactivate S-phase kinase-associated protein 2 via transcription factor SP1 to accelerate malignant progression (16). HBXIP can also promote the metastasis of tongue squamous cell carcinoma and regulate the malignant progression of gastric cancer cells through the PI3K/AKT signaling pathway (17,18). Therefore, targeting HBXIP has been suggested as a potential cancer treatment approach. Germacone, a monocyclic sesquiterpene, has been reported to regulate the cell cycle and apoptosis in renal cell carcinoma by inhibiting HBXIP expression (19). Reduction or loss of HBXIP expression increases the number of cells containing single-phase spindles, which impedes the ability of cells to divide (20). Inhibition of HBXIP expression was reported to reduce tumor drug resistance and knockdown of HBXIP expression sensitized patients with osteosarcoma and liver cancer cell lines to chemotherapy (21).

The carcinogenic mechanism of HBXIP in most tumors has been established, but its role in normal cells has been less well studied. At present, the role of HBXIP in maintaining normal glucose tolerance phenotype and normal embryonic tissue development in mice has been preliminarily studied (22,23). Likewise, HBXIP is involved in DNA damage repair (21). In summary, HBXIP serves roles in both normal and cancer cells. The present review summarizes the current knowledge of HBXIP, including its normal physiological function and role in tumor cells, and provides a reference for subsequent research on HBXIP.

Normal physiological role of HBXIP

mTORC1 is a major growth regulator in humans and is activated by translocation to the lysosomal surface in response to numerous cell signals (2). HBXIP is a membrane protein on the surface of lysosomes and forms a pentameric regulatory complex with P18, P14, MEK partner 1 (MP1) and chromosome 7 open reading frame 59 (C7orf59). This complex serves a key role in activating mTORC1. HBXIP and C7orf59 form the core of this pentameric regulatory complex, which is responsible for the initial nucleation of the complex as well as the stabilization of the P18 conformation, which in turn allows the subsequent binding of MP1 and P14 (2,24). Therefore, loss of HBXIP leads to the formation and dysfunction of this complex, which then inhibits mTORC1 activation and impedes the downstream signaling pathways. For example, the self-renewal and differentiation of embryonic stem cells are regulated by mTORC1 signaling. In mice, knockout of HBXIP causes mTORC1 inactivation, which further affects the differentiation of embryonic stem cells and eventually leads to embryonic lethality (23).

HBXIP has also been reported to act as a transcription coactivator of oncoproteins in tumors and has a similar function in normal cells (22,25,26). HBXIP knockout mice have impaired glucose tolerance and reduced insulin production (22). Furthermore, HBXIP is highly expressed in pancreatic islets, acting as a coactivator of pancreatic and duodenal homeobox transcription factor and forming a complex with neurogenic differentiation 1 to upregulate insulin transcription genes and promote insulin secretion (22). Furthermore, the DNA damage response is an intrinsic signaling network in cells that recognizes and repairs DNA damage (27). Ataxia telangiectasia mutated (ATM) is a potential first-step sensor of DNA damage response, which can regulate downstream phosphorylation of p53, murine double minute 2 and checkpoint kinase (Chk) (28). HBXIP delays or blocks cell cycle progression by activating ATM, phosphorylating Chk and activating the G2/M phase DNA damage checkpoint (21). Therefore, patients with high HBXIP expression may be resistant to chemotherapy by regulating DAN damage repair.

In summary, HBXIP may serve a role at several points in the physiological regulation of cells (Fig. 1). When HBXIP expression is dysregulated, it affects the malignant progression of cancer cells. Therefore, an improved understanding of the physiological functions of HXBIP in normal cells will help to elucidate the mechanisms affected by its dysregulation in a more systematic manner.

Figure 1. Normal physiological effects of HBXIP. Activation of mTORC1 signaling promotes normal differentiation of ESCs. HBXIP is involved in DNA damage repair by activating ATM. In the normal adult pancreas, HBXIP is highly expressed in the pancreatic islets in comparison with other pancreatic tissue and promotes the transcription of insulin. HBXIP, hepatitis B X-interacting protein; mTORC1, mammalian target of rapamycin complex 1; ESCs, embryonic stem cells; ATM, ataxia telangiectasia mutated; Chk2, checkpoint kinase; c-Fos, c-Fos proto-oncogene protein; PDX-1, programmed cell death 1 ligand 1; Neurod1, neuronal differentiation 1Gene; P, phosphorylated.

HBXIP and tumors

Prediction of worse survival in patients with tumors and high expression of HBXIP

In the past decade, studies have reported that HBXIP is highly expressed in breast cancer, esophageal squamous cell carcinoma, colorectal, gastric cancer, renal cancer, liver cancer, tongue squamous cell carcinoma and pancreatic cancer, and its expression associated with the clinicopathological characteristics, prognosis and survival of patients (Table I) (6–14). Furthermore, HBXIP expression is associated with tumor metastasis, stage and survival of different tumor types (6–14). Therefore, high expression of HBXIP often predicts a higher degree of malignancy, and promotes tumor cell proliferation and invasion through different mechanisms.

Table I. Association between cancer type and clinicopathological features with high expression of hepatitis B X-interacting protein.

Table I.

Association between cancer type and clinicopathological features with high expression of hepatitis B X-interacting protein.

First author/s, year		Clinicopathological feature
	Tumor type	Differentiation	Invasion	Stage	Survival	Age	Mechanism	(Refs.)
Zhou et al,	Pancreatic	Association	Association	Association	Association	Negative	Unknown.	(6)
2019	ductal						Cancer cell
	carcinoma						metastasis is
							promoted by
Wang et al,	Colorectal	Not shown	Association	Association	Association	Not shown	epithelial-	(7)
2020	cancer						mesenchymal
							transition
Piao et al,	Gastric	Not shown	Association	Association	Association	Not shown	Cancer cell	(8)
2017	cancer						metastasis is
							promoted by
							regulating
							metabolism and
							post-transcriptional
							translation
Li et al,	Cervical	Association	Association	Association	Association	Not shown	Tumor	(9)
2017	cancer						progression is
							promoted via the
							Wnt signaling
							pathway
Wang et al,	Ovarian	Not shown	Association	Association	Association	Not shown	Co-activation	(10)
2017	cancer						of transcription
							factors promotes
							cancer progression
Xia et al,	Esophageal	Not shown	Association	Association	Association	Not shown	Cancer	(11)
2017	squamous						progression is
	cell						influenced through
	carcinoma						translational level
							regulation
Cheng et al,	Breast	Not shown	Association	Association	Association	Negative	Promotes breast	(12)
2014	cancer						cancer via
							metabolism and
							co-activation of
							transcription
							factors
Guo et al,	Liver	Association	Association	Association	Association	Association	Promotes liver	(13)
2021	cancer						cancer
							by regulating
							level of RNA
							modification
							and translation
Wang et al,	Non-small	Not shown	Association	Association	Association	Not shown	Promotes non-	(14)
2017	cell lung						small cell cancer
	cancer						cells via MEPK
							signaling pathway

Tumor-promoting mechanism of HBXIP

The regulation process from DNA to protein is called gene expression regulation (29), which is ordered in time and space. Gene expression is regulated at multiple stages, including at the chromatin, transcription, post-transcription, translation and post-translation stage. Dysregulation of any of these stages can lead to changes in the protein levels in the cell and affect related physiological processes. HBXIP has been reported to influence the malignant progression of tumor cells at multiple levels (Fig. 2).

Figure 2. HBXIP regulates tumor cells at multiple levels. HBXIP promotes c-Myc histone demethylation through LSD-1 and binds to the MEK2 promoter to promote transcription. HBXIP directly promotes transcription via the miR-18b promoter. HBXIP modifies HIF-1α and c-Myc mRNA methylation through Mettl3. Micro RNAs and long non-coding RNAs can target or be targeted by HBXIP. HBXIP can regulate the malignant progression of tumors by acetylase, phosphorylase or promoting the separation of target proteins from ubiquitin recognition receptors. LSD-1, lysine-specific demethylase 1; HIF-1α, hypoxia-inducible factor-1α; Mettl3, methyltransferase-like 3; HBXIP, hepatitis B X-interacting protein; Keap1, Kelch-like ECH associated protein 1; PVHL, The von-Hippel Lindau tumor suppressor; MEK2, MAP Kinase Kinase2; MEK1, MAP Kinase Kinase1; PD-L1, programmed death ligand 1; PCAF, P300/CBP-associated factor; m6A, N6-methyladenosine; c-Myc, Cellular-myelocytomatosis viral oncogene; c-Fos, c-Fos proto-oncogene protein; HMGA2, The high mobility group protein 2; Hotair, HOX transcript antisense RNA; HDAC6, Histone deacetylase 6; HOXB13, Homeobox B13; MST, STE20-like kinase 1; NMHC-IIA, non-muscle heavy chain myosin IIA; SCD2, synthetic cytochrome c oxidase 2; PDHA1, pyruvate dehydrogenase A1; H3K4, histone H3 Lysine 4 trimethylation; PKCβII, protein kinase βC.

i) HBXIP regulates chromatin and transcriptional processes. Nucleosomes are composed of histones and DNA and are the basic units of chromatin. When transcription occurs, the structure of chromatin is altered in such a way as to allow transcription factors to bind to DNA. Thus, transcriptional activation is closely related to the chromatin environment, and histone H3 modification is the primary mode of chromatin remodeling (30). c-Myc is an oncoprotein that binds to the E-box on the DNA sequence and affects the transcription of thousands of human genes (31). Studies have reported that HBXIP mediates demethylation of the c-Myc histone H3K4 by lysine-specific demethylase 1, with the support of long noncoding RNA (lncRNA) HOX transcript antisense RNA. This causes local DNA oxidation and drives the assembly of the c-Myc transcription initiation complex (32). Promoters are DNA sequences with transcriptional initiation specificity and their methylation is associated with transcriptional inhibition (33). HBXIP induces methylation of the microRNA (miRNA/miR)-18b promoter, thereby inhibiting its transcription and then affecting the expression of subsequent proteins, such as up-regulation of mouse double-minute 2 (MDM) expression, which ultimately degrades P53 and promotes the development of breast cancer (34). HBXIP also directly interacts with promoters to affect the expression of related proteins. Mitogen-activated protein kinase kinase kinase (MEKK) 2 is a member of the MEKK family, which activates extracellular signal-regulated kinase (ERK) 1/2 (35). Chromatin immunoprecipitation has shown that HBXIP directly binds to the promoter of MEKK2 to upregulate its expression and activate downstream ERK 1/2 to regulate the invasion and proliferation of breast cancer cells (36).

ii) HBXIP affects post-transcriptional regulation of related proteins. Eukaryotic transcription products undergo a series of processing and modification steps. Common modifications include N1 methyladenosine, 5-methylcytosine, pseudouracil and N6-methyladenosine (m6A) (37,38). Of these, m6A is the most common in mammals (39) and is mediated by methyltransferase-like 3 (Mettl3). The negative regulation of Mettl3 by miR-let-7g is attenuated by HBXIP through the oncogene Lin-28 Homolog B, thereby increasing the level of Mettl3 in cells. There is also an m6A site in the promoter sequence of HBXIP, which can be modified by Mettl3 to promote transcription of HBXIP and thus produce positive feedback (40). Furthermore, HBXIP mediates the mRNA methylation of several proteins involved in the malignant progression of tumors through the regulation of Mettl3. For example, HBXIP mediates the level of m6A modifications in hypoxia-inducible factor (HIF)-1α mRNA via Mettl3 to promote the metabolic reprogramming of hepatocellular carcinoma (41). Likewise, in gastric cancer, HBXIP modifies the level of methylation of c-Myc mRNA via Mettl3 and promotes expression of c-Myc (42).

Most genes in the eukaryotic genome do not encode proteins, and their transcript products are called noncoding (nc)RNAs, which serve a role in normal physiological and pathological states. For example, miRNAs are members of the ncRNA family, which regulate the expression of target proteins by targeting and interacting with the 3′ untranslated regions of mRNA. This induces the degradation or inhibition of translation of mRNA and affects many processes such as cell proliferation and differentiation, and serves a role in promoting or suppressing cancer (43,44). There is a close relationship between miRNAs and HBXIP levels in tumors. For example, both miR-let-7g and miR-18b are downregulated by HBXIP to promote tumor development (34,40). HBXIP can also inhibit the synthesis of human synthetic cytochrome c oxidase 2 and pyruvate dehydrogenase A1 by upregulating the miR-183/182/96 cluster, thereby reprogramming the glucose metabolism of tumor cells to promote malignant progression (45). Certain miRNAs directly affect the mRNA of HBXIP and serve a role in cancer inhibition. For example, miR-145 targets the noncoding region of HBXIP mRNA, inhibiting its translation and preventing malignant progression of breast cancer (46). Similarly, both miR-520b and miR-548p inhibit HBXIP-induced breast and liver cancer (47,48). lncRNAs are another member of the ncRNA family. LncRNAs are >200 nucleotides in length and serve a role in the degradation and regulation of mRNA or protein stability through numerous mechanisms (49). LAMTOR5-AS1 is a lncRNA located next to the HBXIP gene. LAMTOR5-AS1 expression is positively associated with the age of patients with colorectal cancer. LAMTOR5-AS1 may also affect the expression of HBXIP mRNA by inhibiting the miRNAs hsa-let-7b and hsa-miR-20a (50).

iii) HBXIP regulates the expression of related proteins through post-translational modifications (PTMs). Protein PTMs are the addition of moieties, catalyzed by relevant enzymes, to ≥1 amino acid residues to alter the biochemical properties of a protein (51). Common PTMs include acetylation, ubiquitination and phosphorylation, which can change the stability and activity of proteins (52–54). HBXIP affects the malignant progression of tumor cells by altering the acetylation or ubiquitination of target proteins through several mechanisms, thereby regulating their intracellular abundance and activity (Table II). The ubiquitination-proteasome pathway is one of the major pathways of protein degradation (55). HBXIP can prevent this pathway in three ways: i) The first mechanism is though the activation of acetylases. In esophageal squamous cell carcinoma, HBXIP activates the acetylase PCAF via AKT to acetylate a specific lysine residue of HMGA2, preventing ubiquitination at this site and thereby enhancing its stability (56). HBXIP also maintains the stability of programmed death ligand 1 (PD-L1) by increasing the level of acetylation through the acetylase P300. Notably, HBXIP inhibits the degradation of PD-L1 to increase its intracellular levels. HBXIP also acts as a coactivator of the transcription factor ETS2 which upregulates the expression of PD-L1 (57). However, the mechanism by which HBXIP activates P300 remains unclear; ii) HBXIP can directly bind to the target protein to prevent proteasome-mediated degradation. In non-small cell carcinoma, HBXIP binds to MEK1 preventing its degradation by the proteasome (58); and iii) HBXIP prevents the binding of target proteins to ubiquitin ligase. The von-Hippel Lindau tumor suppressor (pVHL) is a tumor suppressor protein which is part of the E3-ubiquitin ligase complex. PVH2 binds the target protein allowing it to be ubiquitinated (59). A study reported that HBXIP abrogates the interaction between pVHL and H1F-1α inhibiting the ubiquitination and therefore degradation of HIF-1α (45). Similarly, HBXIP reduces binding of E3 ubiquitin ligase adaptor protein Kelch-like ECH associated protein 1 (KEAP1) to nuclear factor erythroid 2-related factor 2 (NRF2) and inhibits ubiquitin regulated degradation of NRF2 (60).

Table II. Hepatitis B X-interacting protein regulates protein post-translational modifications through different mechanisms.

Table II.

Hepatitis B X-interacting protein regulates protein post-translational modifications through different mechanisms.

First author/s, year	Type of tumor	Enzyme	Target protein	Residue	Effect	(Refs.)
Ye et al, 2020	Esophageal squamous cell carcinoma	PCAF	HMGA2	K26	Blocking ubiquitination-proteasome pathway degradation	(56)
Zhang et al, 2021	Non-small cell carcinoma	None	MEK1	Binding		(58)
Xu et al, 2021	Breast cancer	P300	PD-L1	K270		(57)
Liu et al, 2015		None	PVHL and H1F-1α	Promote dissociation		(45)
Zhou et al, 2019		None	Keap1 and Nrf2	Promote dissociation		(60)
Liu et al, 2018		P300	HOXB13	K277	Prevent degradation by the	(62)
Li et al, 2015		HDAC6	MST1	L35	lysosomal pathway	(63)
Zhang et al, 2023		PKCβII	NMHC-IIA	S1916	Enhanced aggressiveness of cancer cells	(64)

[i] PCAF, P300/CBP-associated factor; HDAC6, Histone deacetylase 6; HOXB13, Homeobox B13; MST, STE20-like kinase 1; NMHC-IIA, non-muscle heavy chain myosin IIA; MEK1, MAP Kinase Kinase1; PD-L1, programmed death ligand 1; HBXIP, hepatitis B X-interacting protein; Keap1, Kelch-like ECH associated protein 1; NRF2, nuclear factor-erythroid 2-related factor 2; PVHL, von-Hippel Lindau tumor suppressor; H1F-1α, hypoxia-inducible factor-1; PKCβII, protein kinase βC.

Another major pathway of protein degradation is chaperon-mediated autophagy. This selectively transports proteins to the lysosomes for degradation (61). HBXIP is also involved in this pathway. Unlike the ubiquitin-proteasome pathway, HBXIP mainly regulates the acetylation of target proteins by modulating acetylases. For example, tissue chip technology showed that HBXIP expression in tumor cells was related to HOXB13 and STEM20 like kinase1 (MST1) (62,63); further research into the mechanism found that HBXIP can change the acetylation levels of HOXB13 and tumor suppressor proteinMST1 via the acetylase P300 and Histone deacetylase 6 (HDAC6) to regulate chaperone-mediated autophagy HBXIP also recruits protein kinase CβII to stimulate phosphorylation of non-muscle heavy chain myosin IIA, thereby enhancing breast cancer invasion (64).

HBXIP acts as an oxidative regulator to promote tumor development

Mitochondria are among the main sources of intracellular reactive oxygen species (ROS), which are continuously produced as a byproduct of aerobic metabolism and simultaneously scavenged by the cellular antioxidant mechanisms, thus maintaining a non-toxic levels (65). Under normal physiological conditions, ROS can act as specific molecular regulators of cell signaling and function. For example, one of the more typical modes of ROS regulation is to reversibly oxidize the sulfhydryl group of a target protein to cystine thereby mediating its biological effects. ROS-induced changes in the intracellular oxidation-reduction (redox) status can affect cellular activities, including signaling, metabolism, growth and apoptosis (66,67). However, in pathological conditions, such as when tumors or inflammation occurs, excessive accumulation of ROS usually leads to redox imbalance, causing oxidative stress. Tumor cells increase their antioxidant capacity to adapt to the elevated ROS levels (68,69). HBXIP reduces ROS levels in tamoxifen-resistant breast cancer cells, demonstrating its potential antioxidant capacity (70). The KEAP1-NRF2 signaling pathway is commonly dysregulated in tumor cells to maintain oxidative balance (71). In breast cancer, HBXIP competitively binds to KEAP1 and NRF2, with a significantly higher affinity for KEAP1 than NRF2 (60). Therefore, when HBXIP is highly expressed in tumors, it binds to KEAP1, activates the nuclear displacement of NRF2, and binds to the related antioxidant response element (ARE), thereby improving the antioxidant capacity of tumor cells. Furthermore, there is an ARE sequence in the HBXIP promoter. Therefore, nuclear translocation of NRF2 allows NRF2 to bind to the HBXIP promoter sequence to upregulate HBXIP. The positive feedback between NRF2 and HBXIP increases the antioxidant capacity of tumor cells (72).

HBXIP regulates ferroptosis and promotes tumor development

Ferroptosis induces programmed cell death by catalyzing the lipid peroxidation of unsaturated fatty acids highly expressed on the cell membrane, under the action of divalent iron or ester oxygenase (73). Lipid metabolism disorder is closely related to ferroptosis. Liver X receptor (LXR) is a gene that induces and controls cholesterol homeostasis and adipogenesis. When the LXR receptor binds to its ligands, it recruits nuclear coactivators containing NR motifs to activate target gene transcription. In the absence of ligands, nuclear co-repressors containing (CoRNR) motifs are recruited to repress transcription (74,75). HBXIP, which contains a CoRNR motif in the side chain of the amino acid sequence, activates LXR independently in a ligand-independent manner, thereby upregulating sterol regulatory element-binding protein-1c expression (76). The altered LXR/Sterol regulatory element-binding transcription factor 1 (SREBP-1c) axis can disrupt fatty acid regulation in normal cells, indicating that HBXIP has the potential to regulate cell ferroptosis. Stearyl-CoA desaturase (SCD) catalyzes the conversion of saturated fatty acids to unsaturated fatty acids and its expression prevents ferroptosis (75). HBXIP acts as a coactivator of transcription factor zinc finger protein 263, which binds to the −315/-165 region of the SCD promoter to upregulate SCD expression, prevent ferroptosis and enhance the drug resistance of tumor cells (77). In summary, the relationship between HBXIP and ferroptosis has not been widely assessed, but we hypothesize there is an association between the two and this is worth further exploration.

Other mechanisms of HBXIP tumor regulation

i) Involvement in the regulation of metabolic reprogramming of tumor cells. HBXIP regulation of glucose metabolism reprogramming in tumor cells has been previously elucidated and its mechanisms of action are as follows: First, HBXIP targets the PI3K/AKT axis and its downstream molecule mTOR to regulate glucose metabolism reprogramming in gastric and bladder cancer (18,78); second, HBXIP, as a coactivator of the transcription factor E2F1, directly induces the transcription of pyruvate kinase, which promotes glycolysis (26); third, HBXIP mediates the m6A levels of HIF-1α mRNA to promote transcription and reduces ubiquitination and degradation of HIF-1α, which increases HIF-1α protein levels in cells to modulate glucose metabolism in tumor cells (41,45); and fourth, HBXIP regulates lipid metabolism in tumor cells through the LXR/SREBP-1c/FAS signaling cascade (76).

ii) HBXIP is a co-activator of multiple transcribed genes. Following phosphorylation at Ser26, HBXIP interacts with the leucine zipper domain of c-Fos and translocates from the cytoplasm to the nucleus (79). The leucine zipper domain of HBXIP binds to transcription factors, allowing HBXIP to act as a coactivator to regulate the transcription of downstream related proteins and signaling pathways (79). For example, transcription factors such as E2F1, SP1, c-Myc, STAT4 and CREB have been reported to bind to HBXIP and act on downstream-related genes and proteins to promote tumor development (25,26,80,81).

iii) Involvement in endoplasmic reticulum (ER) stress. When the demand for protein folding exceeds the limit of the ER, ER stress is triggered and the unfolded protein response (UPR) is activated to maintain ER homeostasis (82). Appropriate ER stress can promote the survival of tumor cells (83). HBXIP is a novel UPR factor that can bind to the ER stress protein sensor inositol-requiring transmembrane kinase/endoribonuclease 1α, thereby regulating UPR in the appropriate range to promote tumor cell survival (70).

iv) High expression of HBXIP can cause abnormal activation of multiple signaling pathways: Abnormal activation of the PI3K/AKT signaling pathway in liver, stomach cancer, breast cancer and tongue squamous cell carcinoma promotes the malignant progression of tumor cells (17,18,80,84); the MAPK/ERK signaling pathway can be aberrantly activated by HBXIP in non-small cell lung cancer and breast cancer, thereby promoting tumor cell invasion inhibiting targeting by the immune complement system (36,58); and knockdown of HBXIP can block the Wnt signaling pathway and inhibit the malignant progression of cervical cancer (15).

v) Positive feedback signaling in tumors. HBXIP has positive feedback signaling in multiple types of tumors (Fig. 3). For example, HBXIP upregulates the expression of Mettl3, which methylates HBXIP promoter to upregulate HBXIP protein expression. HBXIP also upregulates the expression of tumor necrosis factor receptor 1, which in turn increases the expression of HBXIP by activating the NF-kB/STAT3 signaling pathway (40,85). In summary, such a positive feedback mechanism could enhance the role of HBXIP in promoting tumor cell proliferation and invasion, or other molecular mechanisms of malignant progression.

Figure 3. Multiple positive feedback processes involving HBXIP. After HBXIP upregulates TNFR1, this activates the NF-κB pathway, which activates STAT3 in the nucleus and activates the HBXIP promoter. After HBXIP upregulates LXRs, activated SREBP-1c stimulates the HBXIP promoter. HBXIP inhibits the inhibitory effect of Lin28b on Mettl3, which methylates the HBXIP promoter to promote HBXIP expression. HBXIP, hepatitis B X-interacting protein; Lin28b, Lin-28 homolog B; TNFR1, tumor necrosis factor receptor 1; NF-κB, nuclear factor-kB; STAT3, signal transducer and activator of transcription 3; LXRs, liver X receptor; Mettl3, methyltransferase-like 3; SREBP-1c, sterol regulatory element-binding transcription factor 1.

Discussion

HBXIP is a membrane protein localized on the surface of lysosomes and is encoded by the Lamtor gene. Under normal physiological conditions, the pentameric complex that includes HBXIP serves an important role in the regulation of mTORC. HBXIP is essential for the normal development of mouse embryos and HBXIP promotes the transcription of insulin transcription factors, thereby maintaining normal cellular glucose metabolism. As an oncoprotein, HBXIP is highly expressed in numerous tumor types and is associated with poor clinicopathological features. Moreover, drug resistance is associated with a high expression of HBXIP protein in different tumors. For example, in estrogen-receptor-positive breast cancer, HBXIP enhances interleukin-6 transcription and maintains appropriate estrogen receptor activation to confer tamoxifen resistance. Furthermore, doxorubicin acts as a tumor suppressor by regulating DNA damage response and inducing apoptosis. However, high expression of HBXIP increase of DNA damage repair and thus serves a role in resistance to doxorubicin-induced DNA damage. In summary, the carcinogenic mechanism of HBXIP should be further studied.

In the present review, three types of mechanisms by which high expression of HBXIP promotes tumor progression were discussed: i) HXBIP promotes tumor development by regulating transcriptional, post-transcriptional and translational processes; ii) HBXIP promotes tumor development as a regulator of oxidative stress; and iii) HBXIP prevents ferroptosis of tumor cells and promotes tumor development. The reprogramming of tumor cell metabolism by HBXIP was also discussed, as well as its role as a coactivator of transcription factors and as a novel effector of UPRs.

Over the past decade, HBXIP has been studied; however, further research is still required to elucidate the relationship between HBXIP and ferroptosis to determine whether HBXIP regulates ferroptosis-related proteins, such as glutathione peroxidase 4 and solute carrier family 7 member 11 to inhibit ferroptosis of tumor cells. Furthermore, the protein function of HBXIP may be involved in interference of the Keap1-NRF2 signaling pathway. In previous studies, direct targeting of the Keap1-Nrf2-ARE signaling pathway was the main strategy to inhibit or activate oxidative stress. For example, the natural compound curcumin enhances cellular antioxidant capacity by directly disrupting Keap1 and thereby activating NRF2 in the nucleus (86). However, the fact that HBXIP competes with NRF2 to bind Keap1 brings new considerations for modulating with this pathway. Future studies should assess a mechanism to inhibit the binding of HBXIP and Keap1, to regulate the level of NRF2 in the nucleus to indirectly regulate the ROS levels to kill tumor cells. Moreover, further research on the interaction between HBXIP and PTM is required.

HBXIP can affect the expression of related proteins through acetylation, ubiquitination and phosphorylation. The diversity and universality of HBXIP, through the different modifications demonstrated in several types of tumors are worthy of further evaluation. The present review demonstrated that the expression of HBXIP and different PTM enzymes verified by tissue chip technology has a good preliminary screening effect, and subsequent testing in different tumor types should be considered to expand knowledge of the relationship between HBXIP and PTM. For the development of drugs targeting HBXIP. Although the mechanism of action of HBXIP in numerous malignant tumors has been established, research on drugs targeting HBXIP is scarce. At present, Germacrone extracted from the traditional herbal medicine Curcuma zedoaria, was reported by Fang et al (19) to inhibit the expression of HBXIP. Therefore, considering traditional Chinese herbal medicine may be a potential direction for the selection of HBXIP targeted drugs in the future. Further research should develop natural or synthetic compounds for the clinical treatment of HBXIP-related tumors.

In conclusion, HBXIP can promote the proliferation, invasion and migration of tumor cells through numerous mechanisms. Inhibition of HBXIP expression has potential therapeutic significance for cancers. Finally, HBXIP has therapeutic potential in tumors, and more in-depth studies are required to further explore its carcinogenic mechanisms.

Acknowledgements

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Funding

Funding: No funding was received.

Availability of data and materials

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Authors' contributions

The original draft of the manuscript was written by LC, manuscript editing and review was performed by LG, TZ and YY. SL and RT revised and edited the final version of the manuscript. All authors have read and approved the final version of the manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

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Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References