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MicroRNAs in hepatocellular carcinoma – therapeutics and beyond

A systematic review

Roy, Gaurav; Roy, Papai

doi: 10.4103/ijssr.ijssr_6_17
Review Article

Hepatocellular carcinoma (HCC) causes major cancer-related deaths worldwide. The current therapeutic strategies pitted against early HCC are woefully inadequate with surgical interventions, radiation therapy, and chemotherapy to suffice for. Therefore, the quest for novel, effective, and decisive screening tools is paramount. In context, microRNAs (miRNAs) have emerged as useful biomarkers in HCC. Accordingly, PubMed, Medline, Embase, and Cochrane databases were explored for relevant literature in English with combination of keywords “microRNA and hepatocellular carcinoma,” “microRNA and diagnosis and hepatocellular carcinoma,” “microRNA and prognosis and hepatocellular carcinoma,” “microRNA and survival and hepatocellular carcinoma,” and “microRNA and therapy and hepatocellular carcinoma” that were extracted till January 2017. Manuscripts relating to long noncoding RNAs and other concomitant small molecules involved in HCC were excluded from the review. Studies revealed a plethora of miRNAs and their altered expression profiles being significantly implicated in the diagnosis, prognosis, recurrence, and overall survival in HCC. Several miRNAs are currently being tested in different phases of clinical trials. Efforts should aim at a better validation and establishment of miRNAs as powerful diagnostic and prognostic investigating aid for HCC. However, despite extensive research, a consensus on the universal set of miRNAs to be used as diagnostic, prognostic, or recurrence markers for HCC is yet to be achieved. In addition, various targeted approaches should focus to reduce the possibility of deleterious off-target effects of miRNAs. On this background, this systematic review discusses latest developments on miRNAs as a marker of diagnosis, prognosis, recurrence, overall survival as well as a therapeutic target in HCC (REVIEW registry216).

Molecular Genetics Laboratory, Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India

Molecular Genetics and Development, Institut de Recherches Cliniques de Montreal, Montreal, Canada

Address for correspondence:Gaurav Roy, Molecular Genetics Laboratory, Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India

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Hepatocellular carcinoma (HCC) constitutes a global health hazard accounting for 90% of primary liver cancers, 1 with risk factors ranging from fatty liver disease, metabolic disorders, chronic alcohol exposure, aflatoxin B1 to hepatitis B virus (HBV) or hepatitis C virus (HCV) viral infections. 2 Recent advances in molecular therapeutics have zeroed in on identifying specific diagnostic and prognostic targets for HCC. In the context, several proteins, long noncoding RNAs (lncRNA), and microRNAs (miRNA) have been reported to exhibit therapeutic efficiency in HCC. 3 On the aforesaid backdrop, this systematic review prospectively embellishes state of the art on miRNA as diagnostic and prognostic assessment modality in the therapeutics of HCC.

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Data Extraction and Selection Criteria

Literature was probed thoroughly in PubMed, Medline, Embase, and Cochrane databases using the combination of keywords “microRNA and hepatocellular carcinoma,” “microRNA and diagnosis and hepatocellular carcinoma,” “microRNA and prognosis and hepatocellular carcinoma,” “microRNA and survival and hepatocellular carcinoma,” and “microRNA and therapy and hepatocellular carcinoma” till January 2017. The scope notes in Medline and Embase were also evaluated that warranted correct subject headings based on definitions.

Only eligible manuscripts in English were retrieved with an in-depth scrutiny on their references for related studies. No restriction was imposed on sample size, population, year of publication, or type of report. Articles pertaining to lncRNAs and other concomitant small molecules implicated in HCC were judiciously excluded from the review. The accuracy of the extracted information was ensured when two investigators (Gaurav Roy and Papai Roy) independently searched data and differences agreed on by a final consensus between them. In addition, this study was fully compliant with the PRISMA Guidelines that included a checklist of aspects incorporated for this systematic review without meta-analysis as designed by the PRISMA Group. 4 Furthermore, our article was registered with the research registry, and subsequently, a unique identifying number (REVIEW registry216) was generated after relevant information pertaining to the nature of our study was systematically filled up.

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Involvement of MicroRNAs in Hepatocellular Carcinoma: An Overview

miRNA s are 20–22 nucleotide long, endogenous, nonprotein-coding RNA molecules that are primarily associated with downregulation of its target genes. Briefly, miRNAs are generally transcribed by RNA polymerase II from the intergenic region or from the antisense orientation of the gene. This primary transcript known as pri-miRNA are generally hundred to thousand base-pairs long. Subsequent internuclear processing by Drosha/Pasha complex converts pri-miRNAs to 50–80 nucleotide long pre-miRNAs with a characteristic stem-loop structure. Contextually, exportin-5 protein is the key molecule involved in the transportation of pre-miRNAs from the nucleus to the cytoplasm. Finally, in cytoplasm, the pre-miRNA undergoes further processing by Dicer to generate an imperfect duplex whereby either strand of the duplex acts as a mature miRNA.

miRNAs target messenger RNAs (mRNA) by complementarity of bases in the 3'-untranslated region (3'UTR) of the mRNA and the miRNA sequence and prospectively recruit mRNAs to the RNA-induced silencing complex that ultimately results in the inhibition of translation or degradation of mRNA. As base-pairing takes place through few bases, one miRNA may target a number of mRNAs, and contrariwise, a single mRNA may be targeted by a number of miRNAs Figure 1. Functionally, miRNAs regulate various biological processes such as apoptosis, differentiation, and development. 5 Studies indicate altered miRNA expression to be associated with the development of several cancers, prion diseases, Alzheimer's condition, and autoimmune disorders. 6 , 7 , 8 , 9

Figure 1

Figure 1

The expression profiles of miRNAs in HCC have illustrated contrasting prospects. Reports have indicated that the abundant miR-122 as evidenced in healthy liver tissues is appreciably downregulated in HCC. 3 , 10 In addition, miR-122 has been shown to influence the stability and transcriptional activity of p53 by modulating cyclin G1 expression. 11 Similarly, miR-26a, downregulated in HCC, targets the positive cell cycle regulators, cyclin D2 and cyclin E2. 12 Contrarily, a number miRNAs that are upregulated in HCC (oncomirs) such as miR-21, miR-221, and miR-222 notoriously inhibit the tumor suppression of PTEN. 13 In this regard, miR-93 has also been demonstrated to inhibit PTEN and CDKN1A, thus activating the oncogenic c-Met/p13k/AKT pathway. 14 Interestingly, a plethora of signaling pathways such as Wnt/β-catenin, Ras, transforming growth factor-β, JAK/STAT, and nuclear factor κB have been found to be affected by miRNA dysregulation in HCC that provides crucial functional insights into the mechanistic role played by miRNAs in HCC. 3

Studies on virus-mediated HCC have illustrated a differential expression of miR-122, miR-19a, and miR-223 by the oncogenic HBx protein of HBV that eventually resulted in cellular proliferation of HCC. 15 The preS2 region of HBV mRNA is targeted by let-7 g which results in its sequestration and upregulation of its targets in host cells. 16 In the context, the third most highly expressed miRNA in liver, miR-199a-3p, has been found to be downregulated in HBV-induced HCC. 17 On the flip side, epithelial mesenchymal transition induced by HCV core protein was restored by overexpression of miR-30c and miR-203a in cell culture and HepG2 xenograft models. 18

Reports have suggested miRNAs as crucial screening tools in the diagnosis, prognosis recurrence and metastasis of HCC. Data have displayed miRNAs to be extremely stable that is evidenced in their retention in serum, plasma, urine and formalin-fixed paraffin embedded tissue samples obtained from patients. This property of stability makes miRNAs a potent biomarker, easily discernible through laboratory investigations. 3

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Micrornas as Diagnostic Markers in Hepatocellular Carcinoma

Current clinical diagnostic methods through alpha-fetoprotein (AFP), ultrasonography, magnetic resonance imaging and computerized tomography usually detect HCC at a late stage of the disease. 19 Therefore, establishing a panel of miRNAs as early diagnostic markers is imperative. A recent report identified seven differentially expressed miRNAs (miR-29a, miR-29c, miR-133a, miR-143, miR-145, miR-192, and miR-505) known as miRNA classifier that predicted HCC earlier than clinical diagnosis. 20 Studies have illustrated significantly elevated serum levels of miR-122 in HCC patients as compared to healthy controls that are suggestive of its use as a marker of the disease. 21 Similar studies depict that the combination of AFP and 3-miRNA panel (miR-92-3p, miR-107, and miR-3126-5p) is an effective diagnostic aid for early-stage and low-level AFP-HCC patients. 22 Likewise, a 13-miRNA panel (miR-375, miR-92a, miR-10a, miR-223, miR-423, miR-23b, miR-23a, miR-342-3p, miR-99a, miR-122a, miR-125b, miR-150, let-7c) has been identified as a novel noninvasive biomarker in HBV-mediated HCC that has paved the way for the diagnosis and differentiation of HBV-induced HCC cases from healthy controls, HCV and subjects with HBV infection without HCC. 23

MiR-1269 has been frequently reported in HCV-induced HCC as compared to healthy controls, HCV-induced cirrhosis, and HBV-induced liver failure. Other upregulated miRNAs in HCV-induced HCC are miR-224, miR-224-3p, and miR-452. However, miR-199a-5p, miR-199a-3p, and miR-199b have been reported to be downregulated in HCV-induced HCC as compared to healthy controls, HCV-induced cirrhosis, and HBV-induced liver failure. 24 A study in Egyptian patients established miR-122, miR-199a, and miR-16 as potential biomarkers of HCV-induced HCC. 25

Exosomes are extracellular vesicles that have been recently recognized as one of the vectors for intercellular communication. Exosomal miRNAs derived from HCC cells have been shown to induce cellular transformation in recipient cells. Studies on miRNA in exosomes derived from HCC cell lines detected 11 exclusive miRNAs in Hep3B-derived exosomes and 20 exclusive miRNAs in PLC/PRF/5-derived exosomes. 26 Another study on serum exosomal miRNA has demonstrated an elevated expression of miR-18a, miR-221, miR-222, and miR-224 in HCC patients as compared to chronic HBV patients and cirrhotic patients and a lowered expression of miR-101, miR-106b, miR-122, miR-195 in HCC patients as compared to chronic HBV patients. 27

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Prognosis of Hepatocellular Carcinoma Through MicroRNA Signatures

Accumulating evidences have displayed miRNAs as a significant prognostic aid in HCC. Differential miRNA expression has been tightly correlated with tumor size, tumor nodule, risk of metastasis, tumor invasion, recurrence, and overall survival in HCC. Studies have illustrated miR-25 to regulate the tumor nodes metastasis staging Figure 2in HCC. 28 Elevated expression of miR-183 in HCC tissues has been associated with large tumor size, positive nodal status, and a higher risk of metastasis. 29 In the same vein, an upregulation of miR-221 has been demonstrated in primary HCC with distant metastasis, whereas the converse is valid for miR-100 expression. 30 , 31 Contrastingly, a downregulation of miR-338 in HCC has been found to be deleterious leading to the development of larger tumors, intrahepatic and distant metastases with extensive vascular invasion. 32 Similar panel of 20 miRNAs has been reported to be concurrent with HCC recurrence and metastasis. 33 Another recent study indicates miR-487 (mediated by heat shock factor 1) as a prognostic marker that promotes proliferation and metastasis of HCC by binding phosphoinositide-3-Kinase regulatory subunit 1 (PIK3R1) and sprouty-related EVH1 domain containing 2. 34

Figure 2

Figure 2

Upregulation of miR-221 and downregulation of miR-214 are associated with recurrence of HCC. 35 , 36 In addition, upregulation of miR-147 and miR-155 and downregulation of miR-19a, miR-886-5p, miR-126, miR-22, and miR-24 have been described to be associated with recurrence following liver transplantation. 37 , 38 However, in HBV-induced HCC, miR-29a-5p acts as a marker for the prediction of early tumor recurrence after HCC resection. 39

Needless to mention, the end-point in cancer research is overall survival. In context, data have predicted an overall shorter survival in HCC by an elevated expression of miR-25, miR-372, miR-155, and miR-182 whereas increased survival has been assessed through downregulation of miR-100, miR-29, miR-10,1and miR-148b. 28 , 31 , 35 , 40 , 41 , 42 , 43 , 44

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Targeted Therapeutics in Hepatocellular Carcinoma-microRNAs as Key Players

Harnessing the therapeutic potential of miRNAs is nowadays much in vogue. As a common practice in cancer therapy, miRNA antagonists such as chemically modified locked nucleic acids (LNA) or antagomirs have been used to inhibit oncomir activity. These miRNA antagonists bind the oncomirs by base-pairing to inhibit their activity. 45 , 46 Studies on animal models have revealed a suppression of the oncomir miR-221 resulting in a significant decrease in tumor number, size, and increased overall survival. 47 Antisense miR-21 co-encapsulated with gemcitabine in PEGylated-PLGA nanoparticles have resulted in increased apoptosis in HCC cell lines. 48 In addition, miravirsen, an anti-miR-122 (a 15-nucleotide LNA) used to treat chronic HCV infection, is currently in phase III clinical trials. 49

Downregulated miRNA activity is nowadays restored by introducing miRNA mimics in cells. Targeted delivery of miR-375 through gold nanoparticles into primary and xenograft mouse models has been shown to be a significant therapeutic vista. 50 In this regard, the use of liposome-based miR-34 mimics is now evidenced in phase I clinical trials. 51

In addition, there are reports of miRNA expression influencing HCC chemotherapy. A study elucidated downregulation of 13 miRNAs binding to adenosine triphosphate-binding cassette (ABC) transporters (ABCA1, ABCC1, ABCC5, ABCC10, and ABCE1) to render chemoresistance in HCC cells by efflux of specific drugs from the cells. 52 Studies have opined that a downregulation of miR-223 regulates ABCB1 expression, thereby resulting in multidrug resistance (MDR). 53

The miRNA expression profile has been found to play a crucial role in the treatment of HCC by interferons (IFNs). Results have shown that an overexpression of miR-146 makes HCC cells resistant to IFN by downregulating SMAD4. 54 However, a decreased expression of miR-26 renders HCC cells sensitive to IFNs. 55 HCC cell lines transfected with anti-miR-21 has been demonstrated to exhibit better clinical response when treated with IFN-α/5-fluorouracil (5-FU) combination therapy. 56 On the other hand, an increased expression of miR-141 in HCC cells is associated with 5-FU resistance, whereas the reverse is true for miR-193a-3p in HCC. 57 , 58

Administration of sorafenib, a multi-kinase inhibitor against HCC, has been reported to modulate miRNA expression. Sorafenib treatment in HCC cell lines resulted in an upregulation of 14 miRNAs. 59 Overexpression of miR-122 in HCC cell lines makes them more sensitive to sorafenib treatment. 60 Contrarily, decreased expression of miR-34a is an indication of sorafenib resistance. 61 In a recent investigation, an artificial lncRNA was generated to overcome sorafenib resistance of HCC by targeting multiple miRNAs. 62

Studies indicate that an overexpression of miR-122 in HCC cells makes them sensitive to doxorubicin treatment. 63 This forced expression of miR-122 also increases sensitivity of HCC cells to adriamycin and vincristine by targeting MDR proteins such as ABC, antiapoptotic Bcl-w, and the cell cycle regulator, cyclin B1. 64 Correspondingly, miR-101 in HCC cells is known to inhibit autophagy and enhance cisplatin-induced apoptosis. 65

Therapeutically, metastamiRs are miRNAs that promote or suppress migration and metastasis of cancer cells, exhibiting significant functional correlation with the prognosis of HCC. Unlike targeted therapy, metastamiRs have been shown to target multiple genes and signaling pathways with an appreciable suppression of cancer metastasis that might futuristically enable an anti-HCC miRNA drug screening and development. 66

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Conclusions and Future Perspectives

Major unresolved issues in early diagnosis and clinical management of HCC, such as inherent and adaptive resistance to common chemotherapeutics together with its rapidly advancing nature, have made HCC one of the most challenging and life-threatening malignancies to contain. 67 Symptomatic HCC continues to be mortiferous and the late presentation of patients to the clinics renders the probability of curative treatment regimen acutely infinitesimal. Therefore, early diagnosis of HCC is critical for the applicability of potentially curative treatments. 2 On the above framework, advancements in establishing miRNAs as diagnostic and prognostic biomarkers for HCC are imperative. A large number of miRNAs have already been suggested as biomarkers in HCC. However, a universal consensus on the specific set of miRNAs to be used in the diagnosis and prognosis of HCC is yet to be arrived at. In addition, unanimity on the nature of biological samples to be analyzed for achieving desired results on miRNAs is still in wilderness. Furthermore, tumor microenvironment, biological behavior of tumors, and variation and sensitivity of miRNA expression depending on the nature and progression of the disease play a pivotal role in the limitation of the applicability of miRNAs as a potential therapeutic aid.

Any molecule to be used as a biomarker for routine clinical use must have easy and cost-effective detection methods. However, currently employed techniques for detection of miRNAs are deep sequencing, arrays, and quantitative PCR, all of which are not only expensive but also require specialized training skills for result analysis. Therefore, future inquests should aim at developing cheaper user-friendly detection practices to facilitate a better validation and establishment of miRNAs as powerful diagnostic and prognostic screening tools for HCC.

Another challenge in using miRNAs as therapeutic targets would be to reduce the undesired off-target effects. Oncomirs or tumor suppressor miRNAs against HCC may also have various functional implications on other organ systems. Hence, it is important to deliver the miRNA antagonists or miRNA mimics to specific tumor sites rather than redundant locales. In context, in a study by Kota et al., a viral vector system was developed that delivered miR-26 specifically to the tumor site in a mouse model. 12 Therefore, targeted approaches should aim to reduce the probability of deleterious off-target effects of miRNAs.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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68. . .;:

    Biomarkers; hepatocellular carcinoma; microRNA; survival

    © 2017 President and Fellows of Harvard College