Global regulation on microRNA in hepatitis B virus-associated hepatocellular carcinoma

Recent work has revealed the causative links between deregulation of microRNAs (miRNAs) and cancer development. In hepatocellular carcinoma (HCC), aberrant expression of miRNAs has been observed, but the molecular mechanisms that contribute to such changes remains to be elucidated. Here, we reported the analysis of miRNA expression in 94 pairs of tumor and adjacent nontumor tissues from HBV-associated HCC in Chinese patients. We found miRNAs were aberrantly expressed in HCC tissues. To investigate the cause of such deregulation, we detected changes in DNA copy number by measuring locus-specific hybridization intensity, and found changes in expression of several miRNAs are correlated with genomic amplification or deletion. For example, the genomic regions of miR-30d and miR-151 were amplified in ～50% of HCC tumor tissues, and the expressions of these miRNAs are significantly correlated with DNA copy number. We also employed cDNA microarray data, and provide evidence that key regulators of the miRNA biosynthetic pathway, including DROSHA, DGCR8, AGO1, and AGO2, are frequently overexpressed in HCC. This study provides molecular clues that may contribute to the global changes of miRNA expression in HCC.     

The functions and targets of miR‐212 as a potential biomarker of cancer diagnosis and therapy

Cancer is a major health problem worldwide. An increasing number of researchers are studying the diagnosis, therapy and mechanisms underlying the development and progression of cancer. The study of noncoding RNA has attracted a lot of attention in recent years. It was found that frequent alterations of miRNA expression not only have various functions in cancer but also that miRNAs can act as clinical markers of diagnosis, stage and progression of cancer. MiR‐212 is an important example of miRNAs involved in cancer. According to recent studies, miR‐212 may serve as an oncogene or tumour suppressor by influencing different targets or pathways during the oncogenesis and the development and metastasis of cancer. Its deregulation may serve as a marker for the diagnosis or prognosis of cancer. In addition, it was recently reported that miR‐212 was related to the sensitivity or resistance of cancer cells to chemotherapy or radiotherapy. Here, we summarize the current understanding of miR‐212 functions in cancer by describing the relevant signalling pathways and targets. The role of miR‐212 as a biomarker and its therapeutic potential in cancer is also described. The aim of this review was to identify new methods for the diagnosis and treatment of human cancers.     

MicroRNAs and intestinal pathophysiology

MicroRNAs (miRNAs) represent an abundant class of endogenously expressed small RNAs, which is believed to control the expression of proteins through specific interaction with their mRNAs. MiRNAs are non-coding RNAs of 18 to 24 nucleotides that negatively regulate target mRNAs by binding to their 3'-untranslated regions (UTR). Most eukaryotic cells utilize miRNA to regulate vital functions such as cell differentiation, proliferation or apopotosis. The diversity of miRNAs and of their mRNA targets strongly indicate that they play a key role in the regulation of protein expression. To date, more than 500 different miRNAs have been identified in animals and plants. There are at least 326 miRNAs in the human genome, comprising 1-4% of all expressed human genes, which makes miRNAs one of the largest classes of gene regulators. A single miRNA can bind to and regulate many different mRNA targets and, conversely, several different miRNAs can bind to and cooperatively control a single mRNA target. The correlation between the expression of miRNAs and their effects on tumorigenesis and on the proliferation of cancer cells is beginning to gain experimental evidences. Recent studies showed that abnormal expression of miRNAs represents a common feature of cancer cells and that they can function as tumor suppressor genes or as oncogenes. Therefore, this diversity of action for miRNAs on several target genes could be one of the common mechanisms involved in the deregulation of protein expression observed during intestinal disorders. In this review, the emergent functions of miRNAs in colorectal cancer and their potential role in the intestinal inflammatory process are discussed.     

The role of upregulated miRNAs and the identification of novel mRNA targets in prostatospheres

TICs are characterized by their ability to self-renew, differentiate and initiate tumor formation. miRNAs are small noncoding RNAs that bind to mRNAs resulting in regulation of gene expression and biological functions. The role of miRNAs and TICs in cancer progression led us to hypothesize that miRNAs may regulate genes involved in TIC maintenance. Using whole genome miRNA and mRNA expression profiling of TICs from primary prostate cancer cells, we identified a set of up-regulated miRNAs and a set of genes down-regulated in PSs. Inhibition of these miRNAs results in a decrease of prostatosphere formation and an increase in target gene expression. This study uses genome-wide miRNA profiling to analyze expression in TICs. We connect aberrant miRNA expression and deregulated gene expression in TICs. These findings can contribute to a better understanding of the molecular mechanisms governing TIC development/maintenance and the role that miRNAs have in the fundamental biology of TICs.     

Disruption of microRNA Biogenesis Confers Resistance to ER Stress-Induced Cell Death Upstream of the Mitochondrion

Global downregulation of microRNAs (miRNAs) is a common feature of human tumors and has been shown to enhance cancer progression. Several components of the miRNA biogenesis machinery (XPO5, DICER and TRBP) have been shown to act as haploinsufficient tumor suppressors. How the deregulation of miRNA biogenesis promotes tumor development is not clearly understood. Here we show that loss of miRNA biogenesis increased resistance to endoplasmic reticulum (ER) stress-induced cell death. We observed that HCT116 cells with a DICER hypomorphic mutation (Exn5/Exn5) or where DICER or DROSHA were knocked down were resistant to ER stress-induced cell death. Extensive analysis revealed little difference in the unfolded protein response (UPR) of WT compared to Exn5/Exn5 HCT116 cells upon ER stress treatment. However, analysis of the intrinsic apoptotic pathway showed that resistance occurred upstream of the mitochondria. In particular, BAX activation and dissipation of mitochondrial membrane potential was attenuated, and there was altered expression of BCL-2 family proteins. These observations demonstrate a key role for miRNAs as critical modulators of the ER stress response. In our model, downregulation of miRNA biogenesis delays ER stress-induced apoptosis. This suggests that disrupted miRNA biogenesis may contribute to cancer progression by inhibiting ER stress-induced cell death.     

Deregulation of signalling pathways in prognostic subtypes of hepatocellular carcinoma: Novel insights from interspecies comparison

Hepatocellular carcinoma is a frequent and fatal disease. Recent researches on rodent models and human hepatocarcinogenesis contributed to unravel the molecular mechanisms of hepatocellular carcinoma dedifferentiation and progression, and allowed the discovery of several alterations underlying the deregulation of cell cycle and signalling pathways. This review provides an interpretive analysis of the results of these studies. Mounting evidence emphasises the role of up-regulation of RAS/ERK, PI3K/AKT, IKK/NF-kB, WNT, TGF-β, NOTCH, Hedgehog, and Hippo signalling pathways as well as of aberrant proteasomal activity in hepatocarcinogenesis. Signalling deregulation often occurs in preneoplastic stages of rodent and human hepatocarcinogenesis and progressively increases in carcinomas, being most pronounced in more aggressive tumours. Numerous changes in signalling cascades are involved in the deregulation of carbohydrate, lipid, and methionine metabolism, which play a role in the maintenance of the transformed phenotype. Recent studies on the role of microRNAs in signalling deregulation, and on the interplay between signalling pathways led to crucial achievements in the knowledge of the network of signalling cascades, essential for the development of adjuvant therapies of liver cancer. Furthermore, the analysis of the mechanisms involved in signalling deregulation allowed the identification of numerous putative prognostic markers and novel therapeutic targets of specific hepatocellular carcinoma subtypes associated with different biologic and clinical features. This is of prime importance for the selection of patient subgroups that are most likely to obtain clinical benefit and, hence, for successful development of targeted therapies for liver cancer.     

MicroRNAs and other small silencing RNAs in cancer

Small noncoding RNAs are key controllers of cellular function, and their deregulation can lead to cancer development and metastatic evolution. This review summarizes the most important examples of small RNAs involved in human cancer and discusses their clinical use as biomarkers and drug targets for diagnosis, prognosis, and treatment of cancer. We also describe the possible mechanisms underlying small RNA-mediated transformation and outline the future describing new small RNA families with great potential in cancer biology.     

MicroRNA-320a suppresses human colon cancer cell proliferation by directly targeting β-catenin

Recent profile studies of microRNA (miRNA) expression have documented a deregulation of miRNA (miR-320a) in human colorectal carcinoma. However, its expression pattern and underlying mechanisms in the development and progression of colorectal carcinoma has not been elucidated clearly. Here, we performed real-time PCR to examine the expression levels of miR-320a in colon cancer cell lines and tumor tissues. And then, we investigated its biological functions in colon cancer cells by a gain of functional strategy. Further more, by the combinational approaches of bioinformatics and experimental validation, we confirmed target associations of miR-320a in colorectal carcinoma. Our results showed that miR-320a was frequently downregulated in cancer cell lines and colon cancer tissues. And we demonstrated that miR-320a restoration inhibited colon cancer cell proliferation and β-catenin, a functionally oncogenic molecule was a direct target gene of miR-320a. Finally, the data of real-time PCR showed the reciprocal relationship between miR-320a and β-catenin's downstream genes in colon cancer tissues. These findings indicate that miR-320a suppresses the growth of colon cancer cells by directly targeting β-catenin, suggesting its application in prognosis prediction and cancer treatment.     

The roles of microRNA in cancer and apoptosis

microRNAs (miRNAs) are highly conserved, non-protein-coding RNAs that function to regulate gene expression. In mammals this regulation is primarily carried out by repression of translation. miRNAs play important roles in homeostatic processes such as development, cell proliferation and cell death. Recently the dysregulation of miRNAs has been linked to cancer initiation and progression, indicating that miRNAs may play roles as tumour suppressor genes or oncogenes. The role of miRNAs in apoptosis is not fully understood, however, evidence is mounting that miRNAs are important in this process. The dysregulation of miRNAs involved in apoptosis may provide a mechanism for cancer development and resistance to cancer therapy. This review examines the biosynthesis of miRNA, the mechanisms of miRNA target regulation and the involvement of miRNAs in the initiation and progression of human cancer. It will include miRNAs involved in apoptosis, specifically those miRNAs involved in the regulation of apoptotic pathways and tumour suppressor/oncogene networks. It will also consider emerging evidence supporting a role for miRNAs in modulating sensitivity to anti-cancer therapy.     

MicroRNA expression profile of colon cancer stem-like cells in HT29 adenocarcinoma cell line

Increasing evidence has suggested cancer stem cells (CSCs) are considered to be responsible for cancer formation, recurrence, and metastasis. Recently, many studies have also revealed that microRNAs (miRNAs) strongly implicate in regulating self renewal and tumorigenicity of CSCs in human cancers. However, with respect to colon cancer, the role of miRNAs in stemness maintenance and tumorigenicity of CSCs still remains to be unknown. In the present study, we isolated a population of colon CSCs expressing a CD133 surface phenotype from human HT29 colonic adenocarcinoma cell line by Flow Cytometry Cell Sorting. The CD133⁺ cells possess a greater tumor sphere-forming efficiency in vitro and higher tumorigenic potential in vivo. Furthermore, the CD133⁺ cells are endowed with stem/progenitor cells-like property including expression of “stemness” genes involved in Wnt2, BMI1, Oct3/4, Notch1, C-myc and other genes as well as self-renewal and differentiation capacity. Moreover, we investigated the miRNA expression profile of colon CSCs using miRNA array. Consequently, we identified a colon CSCs miRNA signature comprising 11 overexpressed and 8 underexpressed miRNAs, such as miR-429, miR-155, and miR-320d, some of which may be involved in regulation of stem cell differentiation. Our results suggest that miRNAs might play important roles in stemness maintenance of colon CSCs, and analysis of specific miRNA expression signatures may contribute to potential cancer therapy.