Hepatocellular carcinoma and microRNA: New perspectives on therapeutics and diagnostics☆
Graphical abstract
Introduction
The liver is the largest internal organ in the human body. It is considered the “metabolic warehouse” and processes a vast number of macro- and micro-nutrients. Secreting bile is another important function of the liver which helps absorb nutrients. Metabolic or nutritional dysregulation can often lead to hepatocellular carcinoma (HCC), the most common form of liver cancer in the world. HCC is highly prevalent in certain areas of the world, especially in China [1]. HCCs are usually correlated with viral hepatitis infections, particularly hepatitis B or C, alcoholism or metabolic syndrome, such as fatty liver disease [2]. In the United States, hepatitis C is the main causative agent for initiating HCC. The survival rate of HCC is low and currently the incidence of HCC is on the rise every year. The all-stage survival rate is 16%, whereas the incidence rate increased by about 12% from 2006 to 2010 [3]. Developing diagnostic and prevention strategies relative to HCC has been an attractive area of research, however, HCC can only be diagnosed at a late stage by currently available serum biomarkers, such as α-fetoprotein (AFP), des-γ-carboxy prothrombin (DCP), and squamous cell carcinoma antigen-immunoglobulin M complexes (SCCA-IgM Cs) [4]. With the late diagnosis, the 5-year survival rate of HCC patients has been estimated to be very low.
MicroRNAs (miRNAs) are endogenous, evolutionarily conserved, noncoding RNAs that have been identified as post-transcriptional regulators of gene expression. Approximately 3% human genome codes for miRNA sequences, and the nucleus/cytoplasm are considered the prime intracellular locations of miRNA processing. It has also been determined that mature miRNAs are part of the RNA-induced silencing complex (RISC) which enables post-transcriptional control of gene expression. miRNAs negatively regulate gene expression, mainly through direct interaction with the 3′ untranslated region (3′-UTR) of corresponding target messenger RNAs (mRNAs). The cleavage of the target mRNA is induced only when miRNA–mRNA target sequence complementarity is established. In the case of partial complementarity, the binding of miRNAs leads to translational repression by inhibiting translation into proteins of the sequence. It is also established that each miRNA can target hundreds of mRNAs, and a particular mRNA transcript can be the target of several different miRNAs.
Numerous investigations have used miRNAs as biomarkers to facilitate the identification, characterization, and mechanistic understanding of chemically-induced carcinogenesis. Analysis of a plethora of research papers indicate that a large majority of protein-coding genes may be directly modulated by miRNAs. Identification of miRNA targets is important for our understanding the functions of miRNAs and their implications in disease development. Most human cancers show dual roles of miRNAs; they can function as oncogenes or tumor suppressor genes during tumor development and progression. Given the fact that, an estimated 30,640 new cases of liver cancer were expected to occur in the US during 2013, and more than 80% of these cases are HCCs, originating from hepatocytes, the need to explore the role of miRNAs in liver cancer appears to be critical. It is also noted that, despite numerous efforts to prevent cancer, an estimated 21,670 liver cancer deaths were observed in 2013. This alarming statistic has prompted intense investigation.
The very first report identifying the association between miRNAs and cancer was published in 2002. This report was based on the fact that miR-15-a and miR-16-1 are located on chromosome locus 13q14, a site frequently deleted in B-cell chronic lymphocytic leukemia cases. After this landmark report, numerous laboratories worldwide have identified aberrant expression of miRNAs in several other types of malignancies, e.g., breast cancer, brain cancer, colorectal carcinoma, HCC, lung cancer (commonly non-small cell lung cancer (NSCLC)), lymphomas, prostate cancer and thyroid cancer [5]. It is now clear that miRNAs play varied roles in different capacities in the carcinogenesis process, including metastasis, invasion, proliferation, cell cycle, and apoptosis. Mapping of miRNAs has disclosed that many of them are localized to fragile regions of the genome, and many miRNAs localized to these regions often have decreased expression in cancer cells. miRNAs target mRNAs and exhibit dual roles (both oncogenic and tumor suppressive) besides participating in a number of different cellular functions. Since normal and tumor cells as well as different tumor subtypes exhibit differential expression of miRNAs, these differences have been extrapolated as prognostic and predictive markers in cancer patients.
In this review, the pathophysiology of HCC, biogenesis of miRNAs and their regulation are discussed, keeping in focus potential application of miRNAs as diagnostic indicators and therapeutic agents. The possible modalities of miRNA delivery to treat HCC are also introduced.
Section snippets
Hepatocellular carcinoma
Hepatocellular carcinoma is the most common form of liver cancer and the third most common cause of cancer-related death. The annual global incidence of HCC is approximately 1 million cases, with a male to female ratio of approximately 4:1 [1]. Although the majority of HCC reported cases occur in Africa and Asia, the incidence of HCC has significantly increased in developed countries over the last few decades [6]. This increase is strongly correlated with increase in migration of chronic
miRNA biogenesis and regulation
miRNAs are small noncoding RNAs of about 20 to 24 nucleotides long which mainly function in posttranscriptional gene regulation [21]. As a regulator, miRNAs silence mRNAs thereby inhibiting the production of the prior coded proteins. Varieties of miRNAs are found in both plants and animals. It is estimated that at least 2000 human miRNAs have been discovered and they are found in almost all human cells. A number of studies associate miRNAs to numerous functions including cell proliferation,
Regulation of signaling network by miRNA association with HCC
miRNAs play a critical role in regulating the HCC tumorigenesis and metastasis signaling networks. Liu et al. found that miR-135a is up-regulated in HCC patients with portal vein tumor thrombus (PVTT) [26]. The same study also found that miR-135a is transcribed by forkhead box M1 (FOXM1) and directly targets suppressor 1 (MTSS1). miR-210 is another up-regulated miRNA in HCC. It was demonstrated that miR-210 can promote the migration and invasion of HCC cells by targeting vacuole membrane
miRNAs associated with HCC diagnosis
Future advances in HCC survival will likely depend in part on early diagnosis of HCC in high-risk patients. The miRNA expression profile could be used for diagnosis of cancers. Those miRNAs can be an individual [72], [73] or a panel [74], [75]. Actually, identification of noninvasive serum biomarkers for the diagnosis of HCC has been under investigation since 1980s. A literature review compared the accuracy of AFP, DCP, and SCCA-IgM Cs in the early diagnosis and in the prognosis of HCC [4]. It
Conclusions and future remarks
In the new millennia, evolving technological applications and novel biomarkers together with molecular biology have clearly paved the way for clinical oncologists to choose infinite therapeutic modalities for a staggering number of cancers. In the future, this period may be recognized as “the golden age of chemotherapy” because of landmark discoveries in cancer detection, diagnosis, and treatments. It is now common that clinical oncologists prefer more personalized treatment strategies to treat
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This review is part of the Advanced Drug Delivery Reviews theme issue on “miRNAs as targets for cancer treatment: Therapeutics design and delivery”.