Interactional role of microRNAs and bHLH-PAS proteins in cancer (Review)
- Authors:
- Published online on: May 15, 2015 https://doi.org/10.3892/ijo.2015.3007
- Pages: 25-34
Abstract
1. Introduction
miRNAs are small (18–25 nucleotides) non-coding RNAs that degrade target mRNA or suppress its translation by specifically binding to the 3′ untranslated region (3′UTR), thus playing a role of gene silencing (1,2). To date, >1,400 different miRNAs have been found in humans and regulate >30% of mammalian gene expression (3,4). At baseline, miRNAs ensure accurate physiological functions, such as growth, development, differentiation and stress. While, abnormal expression induced by a variety of internal and external factors also plays a pivotal role in tumor origin, proliferation, migration and other pathological processes (5,6).
The bHLH-PAS proteins are heterodimeric transcription factors that form a subgroup of the bHLH superfamily. The bHLH-PAS proteins generally consist of two PAS domains that can sense and respond to environmental signals; for example benzo[a]pyrene (B[a]P), 2,3,7,8-tetrachlorodibenzo-r-dioxin (TCDD) or to physiological signals (such as hypoxia) (7). The bHLH-PAS superfamily includes some very important transcription factors such as AHR, the AHR nuclear translocator (ARNT; also known as HIF1β), the AHR repressor (AHRR) and different HIFs. Members of the bHLH-PAS family play a broad range role in physiological and pathological processes and take part in multiple cellular signal pathways (8–10). Recent studies have discovered several selective agonists and antagonists that directly target this multifunctional family, presenting a huge potential as an antitumor drug target (11,12).
In recent years, many studies have shown that AHR and HIF can play pro-tumor or antitumor roles. Moreover, the role of miRNAs in tumor origin and development are also focus of attention. Thus, this review focuses on the complicated interactional mechanisms between miRNAs and certain bHLH-PAS proteins (the HIF and AHR) in many vital events relevant to multiple forms of tumors.
2. miRNAs and bHLH-PAS proteins
Epidemiological and experimental research provides substantial support for the association between bHLH-PAS proteins and miRNAs in cancer (13) (Fig. 1, Tables I and II). miR-210 is a very important HIF associated miRNA that can be found consistently dysregulated in multiple forms of tumors and is involved in many HIFs associated cellular signal pathways (14–16). Similarly to the transcriptional mechanism of protein encoding genes, the transcription of miRNAs from miRNA genes is regulated by transcription factors, including HIFs and AHR. In breast cancer cells, miRNA sequencing data analysis identified 41 miRNAs significantly upregulated and 28 down-regulated under hypoxia. Moreover, study on the transcriptional regulation of miRNA expression by HIFs further illustrated that significantly upregulated miR-210-3p contained a HIF-binding site at its promoter region (17). The promoter regions of miR-155 and miR-373 genes were also found containing HIF-binding site by which hypoxia could promote the transcription of related miRNAs (18). In addition, several transcripts involved in miRNA expressional processes were found to be regulated by hypoxia. For instance, HIF1 regulated the expression of two miRNA transcripts: DICER and AGO4 (17). On the other hand, some miRNAs target HIFs and AHR are involved in the regulation of members in HIFs and AHR signal pathways. Hypoxia regulates the expression of miR-20b, miR-199, miR-210 and miR-424 which can directly target HIFs or control its expression (19–23).
In regards to AHR, Gordon et al reported that the environmental carcinogen B[a]P and TCDD, the xenobiotic AHR ligands, upregulated the expression of a variety of miRNAs in multiple myeloma cells. Importantly, the miR-25 promoter was activated by both B[a]P and TCDD, and this response was mediated by AhR (24).
3. The potential mechanisms
Proliferation and cell cycle
miR-210 and miR-21 are upregulated by HIF1α in a variety of tumors and take part in regulating tumor growth, proliferation and the cell cycle (25). For example, the overexpression of miR-210 induced by HIF1α could be found in melanoma and lung cancer cells, upregulated miR-210 inhibited proliferation of lung cancer (26). While Li et al reported that upregulated miR-210 facilitated tumor proliferation in epithelial ovarian cancer via targeting protein tyrosine phosphatase, non-receptor type 1 (PTPN1) (27). In addition, inhibition of miR-210 caused cell cycle arrest prior to G2/M in melanoma (28). miR-21 promoted proliferation and overrode hypoxia-induced cell cycle arrest at the G1/S transition (29). In vitro, in vivo and pathological study showed that HIF1α was a direct target of miR-199 family, downregulated miR-199a was essential for hypoxia induced proliferation by derepressing the expression of HIF1α and influencing HIF1α mediated the glycolytic pathway in non-small cell lung cancer (NSCLC) (30). While the overexpression of miR-199a and miR-199b, by using virus vectors, significantly downregulated HIF1α and suppressed cell proliferation in hepatocellular carcinoma (HCC) (31) and prostate cancer (32), respectively. Zhang et al demonstrated that miR-135b promoted tumor proliferation and colony formation through targeting factor inhibiting HIF (FIH) and activating HIF1α in head and neck squamous cell carcinoma (HNSCC) (33). In addition, Taguchi et al showed that overexpression of miR-17–92 induced by c-myc directly targeted HIF1α and played a role in cancer cell proliferation (34).
Regarding AHR, Trivellin et al reported that miR-107 was overexpressed in pituitary adenoma samples, and the overexpression of miR-107 inhibited cell proliferation through directly targeting the AHR-interacting protein (AIP) (35). When exposed to B[a]P, the expression levels of miR-320 and miR-494 were upregulated and repressed the expression of cyclin-dependent kinase 6 (CDK6), which regulates cell cycle progression by impacting G1/S transition (36). Yuan et al identified ARNT as a novel target of miR-221, and found that delivery of the miR-221 mimics into primary hepatocytes and overexpression of miR-221 mediated by adeno-associated virus in the mouse liver could significantly promote proliferation by targeting ARNT, and suppressed the cell cycle regulator p27 (37).
Angiogenesis
Angiogenesis plays a key role in tumor growth and metastasis (38). bHLH-PAS proteins regulate several angiogenic growth factors through transcriptional modulation, such as the well-known angiogenesis inducer, the vascular endothelial growth factor (VEGF) (39–41). On one hand, bHLH-PAS proteins contribute to vascular homeostasis under adverse environment including toxins and hypoxia, on the other, bHLH-PAS proteins promote angiogenesis in various types of tumors.
He et al found that miR-199a-5p expression levels were significantly downregulated in arsenic transformed cells, and demonstrated that arsenic promoted tumor growth and angiogenesis due to low expression of miR-199a-5p caused loss of control on its direct targets HIF1α and its downstream target COX-2 in vitro and in vivo (19). In low-oxygen conditions, miR-320 was downregulated by HIF1α in human umbilical vein endothelial cells (HUVECs) and attenuated the inhibitory effect on its target Neuropilin 1, an important regulator of angiogenesis, thus promoting angiogenesis (42). The interaction between HIF and VEGF regulates tumor angiogenesis and enables tumor cells to adapt to different oxygen concentrations (43). Recent studies illustrate miRNAs are also involved in the HIF/VEGF network (20,44,45). For instance, miR-199a and miR-125b were downregulated in ovarian cancer tissues and cell lines and negatively correlated with tumor angiogenesis via HIF1α/VEGF pathway (46). Overexpression of miR-22 inhibited HIF1α expression, repressing VEGF production during hypoxia. Conversely, knockdown of endogenous miR-22 enhanced hypoxia-induced expression of HIF1α and VEGF (47). In addition to the inhibitory effects of miR-503 on angiogenesis through directly targeting two most potent angiogenic factors: fibroblast growth factor-2 (FGF2) and VEGFA (48), miR-128 and miR-145 were demonstrated to attenuate tumor angiogenesis by targeting p70S6K1 and suppressing the downstream signaling molecules HIF1 and VEGF (49,50). When induced by hypoxia, miR-519c resulted in a significant decrease of HIF1α protein levels and reduced the tube formation of HUVECs. Similarly, inhibition of miR-519c by antagonist increased the level of HIF1α protein and enhanced angiogenic activity (51). Moreover, increased HIF2α in hypoxia induced the repression of miR-15–16 and promoted angiogenesis in colorectal carcinoma cell lines (52).
Invasion and metastasis
Zhang et al found that AHR modulator TCDD and the 6-methyl-1,3,-trichlorodibenzofuran (MCDF) inhibited breast cancer cell invasion by inducing the high expression of miR-335 and repressing a target gene of miR-335: SRY-related high mobility group box 4 (SOX4). Knocking down the AHR inhibited the effects of TCDD and MCDF on miR-335 and SOX4 expression, thus confirming AHR-miR-335 interact to inhibit breast cancer cell metastasis (53). Interestingly, SOX4 was also a target gene of miR-138, the expression of miR-138 inhibited ovarian cancer metastasis via suppressing SOX4 and HIF1α, and overexpression of SOX4 and HIF1α effectively reversed the miR-138 mediated suppression of cell metastasis (54). In low-oxygen conditions, decreased miR-199a facilitated the metastasis of ovarian cancer cells due to attenuating the inhibitory effect on HIF1α and HIF2α (55). Zhang et al reported that downregulated miR-145 inversely correlated with HIF2α expression in all 20 neuroblastoma samples. While overexpression of miR-145 suppressed tumor invasion and metastasis in vitro and in vivo by directly targeting HIF2α and promoting the expression of cyclin D1, VEGF and matrix metalloproteinase-14 (MMP-14) (56). miR-23b was demonstrated to induce tumor metastasis by targeting von Hippel-Lindau (VHL) and activating the HIF1α/VEGF and β-catenin/Tcf-4 signaling pathways (57). In addition, downregulation of miR-101 by HIF1α/HIF1β enhanced invasion and migration of prostate cancer cells, which may be attributed to the reduced inhibition of enhancer of zeste homolog 2 (Ezh2) by miR-101 (58).
Apoptosis
As a signature miRNA of hypoxia, miR-210 promoted neuroblastoma cell apoptosis via specifically decreasing anti-apoptotic Bcl-2 (59). The upregulation of miR-21 avoided cell apoptosis in pancreatic cancer cells and ovarian cancer cells (27,29). While lentiviral-mediated downregulation of miR-210 expression in hypoxic HCC cells significantly induced apoptosis through directly targeting apoptosis-inducing factor, mitochondrion-associated 3 (AIFM3) (60). In addition, Shang et al showed that miR-199b negatively regulated HIF1α by targeting its 3′UTR and promoted apoptosis (32).
Triggering the AhR by agonists such as TCDD and B[a] P decreased expression levels of miR-196a depending on AhR response element (AhRE) binding. While suppressing AHR expression induced miR-196a was able to promote cell apoptosis (61).
Metabolism
In low-oxygen conditions, Louis Pasteur identified a metabolic shift from mitochondrial oxidative phosphorylation to glycolysis that result from repression of the tricarboxylic acid (TCA) cycle, mitochondrial electron transport, and oxidative phosphorylation (62). Upregulated miR-210 by HIF plays a pivotal role in the regulation of the components that are necessary for this ‘Pasteur effect’, which can minimize the impact of hypoxia on energy production and benefit tumor growth (63,64). miR-210 caused a shift to glycolysis by controlling a series of components of mitochondrial oxidative phosphorylation, these components included iron-sulfur cluster scaffold homolog (ISCU) (63), COX10 (16), mitochondrial complex I and aconitase (65,66), subunit D of succinate dehydrogenase complex (SDHD) (67), glycerol-3-phosphate dehydrogenase 1-like (GPD1-L) (68). In addition to miR-210, miR-183 upregulated HIF1α by targeting isocitrate dehydrogenase 2 (IDH2): mitochondrial enzymes catalyze the conversion of isocitrate to α-ketoglutarate in TCA cycle (69). Downregulated HIF1α by miR-99a in hepatocarcinoma cells inhibited insulin-induced glucose consumption by suppressing pyruvate kinase M2 (PKM2), a rate-limiting enzyme in the glycolytic pathway (70). miR-203 negatively regulated AHR expression and had a putative binding site in the 3′UTR of indoleamine 2,3-dioxygenase (IDO) (71). IDO is a rate-limiting enzyme in extrahepatic catabolism of tryptophan, thus miR-203 may be involved in AHR/IDO axis-mediated metabolism of tryptophan (72).
Inflammation and immunity
Wang et al reported that there was a negative-feedback between miR-210 and HIF1α and they could regulate each other. When induced by hypoxia, miR-210 negatively regulated HIF1α expression and TH17 cell differentiation through reducing HIF1α transcript abundance and the proportion of cells producing inflammatory cytokines, which could limit immunopathology (73). miR-17 and miR-20a mediated post-transcriptional suppression of HIF1α and HIF2α expression in tumor-associated monocytes and macrophages and played an important role during a wide range of cellular physiological as well as pathophysiological processes such as monocyte-to-macrophage differentiation (74,75). Csak et al revealed that downregulation of miR-122 attenuated the inhibitory effect on HIF1α and played a pathogenic role in steatohepatitis (76).
Bleck et al reported that upregulated miR-375 by environmental pollutants could target AhR and downregulate its expression, thus regulating a pivotal cytokine, thymic stromal lymphopoietin (TSLP), which associated with innate and Th2 adaptive immune disorders (77). The overexpression of miR-132/212 cluster induced by AHR promoted differentiation of Th17 cells by targeting a negative regulator of Th17 differentiation, the B-cell lymphoma 6 (78).
Stem cells
Stem cells are found in all multicellular organisms, that can self-renew and differentiate into diverse specialized cell types, and cancer stem cells are critical drivers of tumor progression (38). Yang et al found that hypoxia led to induction of HIF2α and miR-210 in glioma stem cells (GSCs), while knocking down of miR-210 decreased stemness, viability, neurosphere formation capacity, invasive capacity and induced differentiation, apoptosis, G0/G1 cell cycle arrest of hypoxic GSCs, and participated in regulating myc-antagonist (MNT) protein expression and caspase-3/7 activity (79). The enhancement of peroxisome proliferator activated receptor-α (PPARα) and HIF1α interplay in breast cancer stem cells sustained expression of the pro-inflammatory cytokine interleukin-6 (IL-6), the hypoxia survival factor carbonic anhydrase IX and the plasma lipid carrier apolipoprotein E. Moreover, the PPARα/HIF1α interplay was regulated by miR-130b through targeting DDX6 (a HIF1α translation inhibitory protein) and miR-17-5p via directly targeting PPARα (80). Overexpression of miR-21 induced by HIF1α played a positive role for epithelial-mesenchymal transition (EMT), invasion and migration of breast cancer stem cell-like cells (81).
4. Clinical application
The resistance of hypoxic cells to radiotherapy and chemotherapy is a major problem in the treatment of cancer. Induction of miR-210 by HIF1α in hypoxia conferred resistance to radiation via rapidly repairing DNA double-strand breaks after radiation in NSCLC cells (14). The induction of miR-210-3p by HIF1α in GBM cells showed increased resistance to temozolomide (a chemotherapeutic drug) mediated death while miR-210-3p inhibition made cells more sensitive (13). Inhibition of miR-566 was demonstrated to sensitize GBM cells to nimo-tuzumab by targeting VHL and activating the β-catenin/HIF1α complex which can suppress the activity of epidermal growth factor receptor (EGFR) pathway (82). Bao et al reported that the treatment of pancreatic cancer cells with a novel synthetic derivative of curcumin showed an obvious antitumor effect through decreasing gene expression of miR-21, miR-210, IL-6, HIF1α, VEGF under hypoxia (83,84). In low-oxygen conditions, overexpression of miR-155 induced by HIF1α enhanced radioresistance in lung cancer cells and correlated with poor patient prognosis (85). Pyrrolopyrazine metabolite of oltipraz, a cancer chemopreventive agent, was found to play its antineo-plastic function via inducing miR-199a-5p and miR-20a and these two miRNAs mediated inhibition of HIF1α by preventing its de novo synthesis (86). A case-control study including 35 matched HCCs and cirrhosis tissues showed that under-expressed miR-199b regulated by the upregulation of HIF1α in HCCs was inversely correlated with survival and directly correlated with the malignant status of HCC patients (87).
Hu et al demonstrated that upregulation of miR-302 in response to tranilast treatment was dependent on AHR, which was able to bind to miR-302 promoter and active its expression (88). Transcriptionally activated miR-125b by nuclear factor erythroid-2-related factor 2 (Nrf2) served as an inhibitor of AhRR and attenuated its control on AhR, thus, upregulated AhR inhibited p53 activity by targeting an inhibitor of p53 (Mdm2) and contributed to protecting the kidneys from cisplatin-induced injury (89).
5. Conclusions and future directions
There is increasing evidence that the bHLH-PAS proteins and its ligands play important roles in cell normal homeostasis and malignant tumor formation. miRNAs can consistently and rapidly sense and respond to environmental and physiological signals (such as B[a]P and hypoxia) by regulating multi-variety of genes and influencing numerous components of cellular signaling pathways extensively and simultaneously, thus research on the interactional role of miRNAs and bHLH-PAS proteins is worthy to clarify the mechanism that underlies the regulation of these environmental and physiological signals. However, the complicated physiological and pathophysiological molecular mechanisms between miRNAs and bHLH-PAS proteins are still unclear. Therefore, further study is needed to uncover the basic mechanisms and should focus on the following directions. First, we need to find more miRNAs and demonstrate their target genes and functions involved in bHLH-PAS proteins. Then, inflammation and stem cells are very valuable and promising fields in cancer. Further in-depth investigations are needed to understand the underlying mechanisms of this interaction in stem cell transformation, CSCs maintainence, and the relationship between inflammation and cancer. The ultimate goal is to look for specific diagnostic markers and selective preventive and therapeutic drugs thus promoting anticancer pharmaceutical development and benefit the prognosis of cancer patients.
Acknowledgements
This study was supported by the National Natural Science Foundation of China (grant no. 31270532) and Central College Basic Scientific Research Foundation of Lanzhou University (grant no. lzujbky-2013-m04).
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