MicroRNA-122 in human cancers: from mechanistic to clinical perspectives

MicroRNAs (miRNAs) are small noncoding RNAs of approximately 22 nucleotide (nt) that are known to have a significant role in the regulation of the post-transcriptional level of messenger RNAs (mRNAs) [1, 2]. MiRNAs are 22 nt noncoding RNAs recognized to play a crucial function in the post-transcriptional control of mRNA [3‐5]. MiRNAs are usually generated from transcripts of incipient primary miRNAs (pri-miRNAs) through two successive hairpin-shaped precursors (pre-miRNAs) [6]. Pre-miRNAs are transported from the nucleus to the cytoplasm by exportin 5 (XPO5) and cleaved by DICER. The ensuing small RNA duplexes are loaded with Argonaute (AGO) proteins that favorably conserve only one strand of the mature miRNA while taking out the other strand. Together with other molecules like GW182, AGO that has been loaded with miRNA may produce an effector complex known as the RNA-induced silencing complex (RISC). RISC triggers translational repression by interacting with complementary sequences in the 3ʹ-untranslated region (3ʹ-UTR) of target gene mRNAs [7]. As a consequence of this, variations in the levels of miRNA expression have a significant influence on human health as well as the progression of diseases such as cancer. In this regard, Volinia et al. conducted a microarray study and found that miRNAs play a significant role in the carcinogenic process of solid tumors. These findings provide evidence for the function of miRNAs as either dominant or recessive cancer genes [8].

Initial analysis of miR-122 revealed it to be conserved in 12 different species, including humans, frogs, and zebrafish [9]. Since September 2011, the miR-122 expression has been investigated in 18 species, which are all vertebrates. In humans, miR-122 originates from a single genomic region located on chromosome 18. The human miR-122 locus is located in an isolated region of noncoding RNA exons. The pri-miR-122 gene was discovered initially as hcr, a noncoding RNA, and was recently described in depth. The 7.5 kb precursor transcript is created during pri-miR-122 synthesis, and it is subsequently spliced to form the 4.5 kb pri-miR-122, as shown by the localization of the transcription start site and 3' end. The miR-122 core promoter is very well-conserved and has characteristics indicative of a pol II promoter. The liver-enriched transcription factor hepatocyte nuclear factor 4 (HNF-4), which promotes miR-122 production, has a conserved target location there. In the adult liver, miR-122 is expressed at around 66,000 copies per cell, making it one of the most abundant miRNAs in the body [10]. There are no known paralogs of the mature form of miR-122, and its sequence is conserved across all species where it has been found, suggesting that its entirety is crucial to its function. The very liver-specific expression pattern of miR-122 was also shown to be retained across multiple species when it was investigated using in situ hybridization in zebrafish [11].

MiR-122 is involved in a broad range of cellular processes and interacts with many other molecules [12]. Hepatocyte nuclear factor 4A (HNF4A) is a transcription factor that has been shown to control miR-122 via targeting NF-кB-inducing kinase (NIK). Evidence is shown that HCV infection causes an upregulation of NIK expression and downregulation of HNF4A and miR-122 [13]. It has been established by Long et al. that miR-122 inhibition protects hepatocytes against lipid metabolic disorders like Non-alcoholic fatty liver disease (NAFLD) by decreasing lipogenesis and enhancing Sirt1 and AMP-activated protein kinase (AMPK) activity [14]. Additionally, ZW Zhang et al. investigated miR-122’s function in cardiomyocyte apoptosis and found that it has an inductive influence in this process, perhaps because of its influence on caspase-8 [15].

MiRNAs have emerged as a new cell component with variable expression in human cancers throughout the last several years of study. Among the miRNAs, miR-122, miR-206, miR-21, miR-210, miR-223, miR-34a, miR-22, miR-25, miR-320, miR-150, miR-200c, miR-451 and miR-424 have been extensively studied in various cancers [16, 17]. Targeting a variety of genes in human malignancies, miR-122 has the potential to act either as an oncogene or a tumor suppressor. MiR-122 is aberrantly expressed in various tumors, including breast cancer, lung cancer, bladder, leukemia, liver cancer, colorectal cancer, ovarian cancer, and esophageal, acting as both a tumor promoter and tumor silencer. Furthermore, miR-122’s deregulation and aberrant expression in carcinogenesis and tumor development of various cancer types suggest it may be helpful as a diagnostic and/or prognostic marker for human cancer. The miR-122 may also increase the sensitivity of tumor cells to chemotherapy agents. In light of these results, miR-122 is a potential novel therapeutic target and diagnostic/prognostic molecular marker for cancer. As a result, the present review offers a thorough introduction to miR-122 and its role in human cancers, shedding light on this role and assisting in the development of targeted therapeutics (Fig. 1).

Delayed cancer diagnosis and inefficient cancer prognosis determination are problems faced in cancer diagnosis and treatment. MiRs, especially miR-122, have shown a promise in cancer diagnosis and prognosis. In this context, in a large and well-characterized sample of CCA patients receiving tumor excision, Loosen et al. also sought to assess the diagnostic and prognostic utility of miR-122. Their research revealed that miR-122 analysis offers a promising method for the diagnosis of CCA, even in its earliest stages, and that a post-operative decrease in miR-122 serum concentrations may be a sign of a positive outcome and valuable in identifying patients who will recover well from extensive liver surgery [73]. Beside, Mazza et al. sought to discover new miRNAs in plasma that might be used to distinguish between PanC and healthy individuals (HS) in comparison to CA19-9, as well as to forecast the clinical phenotypes and fates of the patients. They concluded that higher plasma miR-122-5p is associated with more adverse clinical outcomes and prognosis [74]. Notably, the expression of miR-122 and its role in glioma diagnosis and prognosis was studied by Tang et al. They discovered that miR-122 expression was dramatically downregulated in the plasma of glioma patients compared to healthy people and that low miR-122 expression was associated with a poor prognosis. As a result, miR-122 may function as a standalone prognostic factor to predict a poor glioma prognosis [75]. Importantly, the expression of miR-122 in LC patients before and after chemotherapy has been quantified by Zhan et al. and their prognostic significance was assessed. They discovered lower miR-122 expression levels in LC tissues, demonstrating their ability to identify malignant tumors from surrounding tissues. They also discovered that sorafenib chemotherapy boosted its levels in the peripheral blood and that miR-122 predicted how well sorafenib chemotherapy worked. Next, the researchers observed that low levels of miR-122 were linked to decreased 5-year survival rates and were independent risk factors for shorter survival in LC [76]. Furthermore, Akuta et al. through the long-term analysis of successive liver biopsies, found that miR-122 circulation dynamics in Japanese individuals with histopathologically diagnosed NAFLD and severe fibrosis stage could predict liver cancer and mortality [77]. Moreover, in order to determine whether plasma levels of particular miRNAs are related to distant metastasis (DM) in gastric cancer, Chen et al. conducted an extensive research study. Using miRNA microarray screenings and additional qRT-PCR confirmation, they discovered that miR-122 expression was considerably lower in patients with gastric cancer with distant metastases (GC/DM) compared to GC/NDM, and greater plasma levels of miR-122 in GC predict a favorable prognosis. This suggests that a reduction in circulating miR-122 may aid in the early diagnosis of DM in GC [78]. Similarly, S Maruyama et al. looked into the clinical use of AFPGC-specific miRNA for patient monitoring and prognostication. Their results unmistakably showed that AFPGC tissues had much higher levels of miR-122-5p expression than normal and non-AFPGC tissues. Additionally, compared to plasma samples from healthy volunteers and patients without AFPGC, patients with AFPGC had greater expression levels of this miRNA, which was somewhat linked with plasma AFP levels. MiR-122-5p may be helpful as a prognostic biomarker, particularly for liver metastasis in this small GC subgroup, because tissue expression levels of the gene showed a greater connection with malignant potential than plasma AFP levels in AFPGC patients [79]. In addition, Maierthaler et al. investigated the potential predictive usefulness of circulating miR-122 for CRC. They discovered that miR-122 might be particularly useful for predicting metastasis and recurrence in non-metastatic CRC patients and tracking their therapy (especially liver metastasis). Additionally, modifying the course of treatment based on the prognosis may increase the likelihood that the patients will survive [80]. Therefore, we hypothesize that miR-122 can also be used as a prognostic biomarker in addition to its diagnostic role.

Resistance to tumor therapy is challenging in cancer treatment due to the daunting range of resistance mechanisms. Cumulative evidence showed that miR-122 was correlated with chemotherapy resistance, suggesting that it might serve as a candidate and promising biomarker for drug resistance. This will be presented in the following section (Fig. 3).

Sorafenib resistance: Turato et al. examined how miR-122 and SerpinB3 affected HCC cell phenotype and sorafenib resistance. Their luciferase experiment and bioinformatics analysis showed that SerpinB3 mRNA and miR-122 interact. In addition, transfection of miR-122 reduced SerpinB3 mRNA and protein levels in HepG2 cells that overexpressed SerpinB3, and suppression of miR-122 boosted SerpinB3 expression. They also found that overexpressing miR-122 enhanced susceptibility to sorafenib in treated cells but not in cells overexpressing SerpinB3. Finally, they found that anti-miR-122 transfection improved cell viability in sorafenib-treated Huh-7 cells. Their research led them to conclude that miR-122 binds to SerpinB3 and that low levels of miR-122 are linked to SerpinB3 positive and a stem-like phenotype in HCC. In this manner, miR-122 replacement treatment with sorafenib merits consideration as a therapeutic option in SerpinB3-negative HCCs [81]. Sorafenib resistance in HCC cells was also studied by Xu et al. Expression of the liver-specific miR-122 was shown to be considerably lower in sorafenib-resistant cells, as determined by miRNA microarray analysis. They found that drug-resistant cells could be rendered responsive to sorafenib and caused apoptosis with overexpression of miR-122. In addition, they demonstrated that the Insulin-like growth factor 1 receptor (IGF-1R) is a target of miR-122 and that activation of IGF-1R by IGFI or IGFII inhibited miR-122-induced apoptosis. Their results demonstrated that the activation of IGF-1R caused sorafenib resistance through ectopic down-regulation of miR-122, which counteracted the drug’s tendency to induce apoptosis. Their follow-up experiments showed that down-regulation of miR-122 led to IGF-1R activation, leading to RAS/RAF/ERK signaling activation, all of which were linked to drug resistance. Thus, abnormal miR-122 and IGF-1R expression significantly determine sorafenib tolerance [82].

Oxaliplatin resistance: Wang et al. looked into the causes of colorectal cancer’s medication resistance. In vitro and in vivo experiments demonstrated that oxaliplatin-resistant cell exosomes transported circular RNA hsa_circ_0005963 (termed ciRS-122) to susceptible cells, where it stimulated glycolysis and drug resistance by miR-122 sponging and upregulating PKM2. Furthermore, exosomal si-ciRS-122 was demonstrated to be effective in vivo at decreasing glycolysis and reversing oxaliplatin resistance by regulating the ciRS-122-miR-122-PKM2 pathway [83]. Furthermore, Hua et al. investigated how miR-122 affected CRC’s ability to become oxaliplatin-resistant. They found that an X-linked inhibitor of apoptosis protein (XIAP) was expressed at significantly higher levels in oxaliplatin-resistant SW480 and HT29 cells (SW480/OR and HT29/OR) compared with normal SW480 and HT29 cells and that miR-122 expression was significantly lower in SW480/OR and HT29/OR. Overexpression of XIAP was shown to contribute to oxaliplatin resistance in CRC cells, and the authors showed that this was partly due to the downregulation of miR-122. They followed this by discovering that restoring miR-122 expression in SW480/OR and HT29/OR cells might make them more vulnerable to apoptosis induced by oxaliplatin by suppressing XIAP expression. Thereby, miR-122 reduced oxaliplatin resistance in CRC by targeting XIAP, leading the researchers to infer that XIAP overexpression in CRC cells is to blame for the development of acquired resistance to the oxaliplatin [84]. Moreover, Cao et al. investigated miR-122’s role in HCC’s oxaliplatin resistance. They discovered that miR-122 was decreased in HCC cells but that up-regulating miR-122 or inhibiting Wnt/-catenin signaling boosted apoptosis and made HCC cells more sensitive to OXA. Furthermore, their molecular analysis showed that miR-122 targeted and suppressed the Wnt/-catenin pathway, while β-catenin linked to the MDR1 promoter and boosted its transcription. Thereby, through downregulation of the Wnt/-catenin pathway, miR-122 reduces MDR1 expression and makes HCC more sensitive to OXA. As a result, miR-122 represents an exciting new therapeutic target for the treatment of HCC [85].

Radioresistance: Perez-Aorve et al. investigated the critical functions that miR-122 plays in radioresistant breast cancer and the processes underneath its function. They discovered 16 deregulated miRNAs using differential expression profiling assays in obtained radioresistant breast cancer cells, among which miR-122 was found to be increased. Functional investigation revealed that miR-122 is upregulated in radioresistant breast cancer to enhance cell survival and that miR-122 controls responses to radiation in a cell-phenotype-dependent way, serving as both a repressor and an oncomiR [86]. Moreover, miR-122-5p and CDC25A were examined by Ding et al. to see how they were expressed in cervical cancer cells and how they affected the cells' radiosensitivity. In cervical cancer tissues and cells, they revealed that miR-122-5p is poorly expressed while CDC25A is substantially expressed. They established CDC25A as a target of miR-122-5p using the TargetScan database and in vitro studies, including a dual-luciferase reporter test. Furthermore, X-ray radiation has been demonstrated to increase CDC25A’s expression, increasing radiation resistance in cervical cancer cells. However, overexpression of miR-122-5p or suppression of CDC25A renders cervical cancer colonies unable to survive and causes them to undergo apoptosis. Consequently, miR-122-5p targets CDC25A, causing cervical cancer cells to become more radiosensitive [87].

Resveratrol resistance: Zhang et al. designed experiments to investigate the functional role of resveratrol in MCF-7 cells (low-invasive breast cancer) concerning Adriamycin chemosensitivity and identify the mRNAs that resveratrol targets and the essential proteins that are involved in cellular activity. They discovered that by manipulating the critical suppressor miR-122-5p, adriamycin-resistant breast cancer cells were sensitive to resveratrol’s chemotherapeutic effects, with cell cycle arrest and apoptosis being the most notable effects. Additional miRNA manipulation using miR-122-5p mimics or inhibitors revealed that miR-122-5p significantly affected the regulation of critical antiapoptotic proteins (B-cell lymphoma 2 [Bcl-2]) and cyclin-dependent kinases (CDK2, CDK4, and CDK6) in resveratrol-resistant breast cancer cells. Therefore, miR-122-5p targets Bcl-2 and CDKs in breast cancer cells, which assists in cell-cycle arrest [88].

Doxorubicin (DOX): Doxorubicin (DOX) resistance in hepatocellular cancer cells was investigated by Pan et al. In contrast to parental Huh7 cells, doxorubicin-resistant Huh7 (Huh7/R) cells showed a down-regulation of miR-122, indicating miR-122 is involved in the chemoresistance. Using a luciferase reporter assay, they demonstrated that PKM2 is the direct target of miR-122 and that glucose metabolism is dramatically increased in Huh7/R cells. Their follow-up investigations revealed that miR-122 overexpression in Huh7/R cells restored doxorubicin resistance via inhibiting PKM2, resulting in the doxorubicin-resistant cancer cells' apoptosis. They concluded that doxorubicin resistance is associated with aberrant glucose metabolism and that miR-122-induced suppression of glycolysis may be a functional therapeutic approach for treating doxorubicin-resistant hepatocellular cancer [89].

Docetaxel resistance: Zhu et al. looked into the function of miR-122 in the chemoresistance of PCa cells and the possible mechanisms. Their findings showed that miR-122 could reverse the resistance of LNCaP/Docetaxel cells to docetaxel and that miR-122 overexpression might increase docetaxel-induced apoptosis in PCa cells. This may be due to miR-122’s ability to regulate its target protein PKM2 by binding to the 3'-UTR. These results establish a causal relationship between miRNAs and PCa chemoresistance, suggesting that miRNA-122 targeting may represent a unique therapeutic approach for PCa chemoresistance [90].

Numerous cancers include a small population of cancer stem cells, cells able to self-renew and differentiate. Inappropriate control of stem cell self-renewal is necessary for the emergence and development of cancer. In addition, the presence of cancer stem cells is likely responsible for resistance to standard cancer therapies and recurrence in patients. A better knowledge of the biology and processes linked with cancer stem cells may lead to better cancer therapies and, maybe, a cure. There is mounting evidence that miRNAs have a role in deregulating cancer stem cells. Recent research suggests that miR-122 plays an essential role in cancer stem cell activity by regulating several proteins (Fig. 4). In this context, Song et al. sought to identify the functional relevance of miR-122 in CD133 ( +) liver CSCs and CD133 (−) cells. Their findings demonstrate that CD133 ( +) hepatocellular CSCs differ from CD133 (−) cells in their metabolic profile, with the former preferring glycolysis over oxidative phosphorylation. Their results showed that blocking Pyruvate Dehydrogenase Kinase 4 (PDK4) and Lactate dehydrogenase A (LDHA) significantly reduced CD133 + stemness features and helped patients overcome sorafenib resistance (chemotherapy medication currently used for hepatocellular cancer). They also showed that CSC features, such as an increase in the CD133 ( +) cell population, stemness gene expression, and spheroid formation, are induced in CD133 (−) cells by the glucose and lactate addition. Through targeting PDK4, their active investigations demonstrated that miR-122, which is abundantly expressed in the liver, inhibits CSC features. According to their claims, enhanced glycolysis is associated with CD133 ( +) stem-like features, and metabolic reprogramming with miR-122 or PDK4 may be a cutting-edge treatment option for hepatocellular carcinoma [91]. Similarly, Gasmi et al. proposed that miR-122 promotes LPC transition into a CSC phenotype, which may play a role at the beginning of liver cancer. Their study provided in vitro proof that long-term IL-17 activation of LPCs caused them to develop into CSCs. Indeed, they gained the ability to express CSC markers and to engage in self-renewal, as shown by an increase in their capacity to form spheroids. Using miRNome analysis, they determined that following chronic treatment with IL-17, miR-122 expression in LPCs decreased by 90%. In an immunodeficient mouse model, they discovered that ectopic engraftment of LPCs in an IL-17-enriched environment triggered tumor formation with an aggressive character. As a result, LPCs are more likely to develop into CSCs after exposure to the cytokine IL-17 over an extended period. Thus, methods that target IL-17 reduce CSC incidence and liver tumor development via miR-122 restoration [92]. Furthermore, Gao et al. investigated the role of exosomal lncRNA urothelial cancer-associated 1 (UCA1) in modulating SOX2 expression in CC stem cells (CD133 + CaSki) by sponging miR-122-5p. CC stem cells (CD133 + CaSki) were discovered to have increased UCA1 and SOX2 and decreased levels of miR-122-5p. Exosomes were discovered to inhibit apoptosis in CD133 + CaSki cells while encouraging migration, invasion, and proliferation. Subsequent functional experiments showed that inhibiting UCA1 or increasing miR-122-5p degraded SOX2 expression, lowered invasion, migration, and proliferation of CD133 + CaSki cells, accelerated apoptosis, and decreased the tumor volume and weight in nude mice. Thus, their findings imply that exosomes transporting UCA1 as a ceRNA of miR-122-5p enhance the expression of SOX2, thus influencing CC stem cell self-renewal and differentiation [93]. The role of lncRNA-SOX2OT and potential molecular pathways by which it affects the biological behaviors of glioblastoma stem cells (GSCs) were further clarified by Su et al. They used real-time PCR to show that SOX2OT expression was elevated in glioma tissues and GSCs. They found that knocking down SOX2OT reduced GSC proliferation, migration, and invasion while increasing their susceptibility to apoptosis. MiR-122 was shown to be down-regulated in both human glioma tissues and GSCs, and it was found to exhibit tumor-suppressive effects by reducing GSC proliferation, motility, and invasion and increasing their susceptibility to apoptosis. Using a dual-luciferase reporter assay, they discovered that SOX2OT is linked to miR-122, and they also discovered that knocking down SOX2OT significantly upregulated miR-122 expression in GSCs. SOX3 and TDGF-1 were both upregulated in human glioma tissues and GSCs. Furthermore, knocking down SOX3 impeded GSC growth, migration, and invasion, increased GSC mortality, and reduced TDGF-1 expression by interacting directly with the TDGF-1 promoter. MiR-122 over-expression reduced SOX3 expression by targeting its 3'UTR, whereas reduction of SOX3 suppressed SOX2OT expression by binding to the SOX2OT promoter directly, creating a positive feedback loop. Notably, reduced proliferation, migration, and invasion of GSCs, increased apoptosis in GSCs, and decreased activity in the JAK/STAT signaling pathway were all significant results of TDGF-1 knockdown. As a result, the SOX2OT-miR-122-SOX3-TDGF-1 pathway establishes a positive feedback loop and governs the biological activities of GSCs; this knowledge may lead to a new approach to treating gliomas [94]. Therefore, correcting miR-122 dysregulation in cancer stem cells with genetic techniques may avert invasive malignancy.