| Hepatocellular carcinoma (HCC) is one of the most common human malignancies in the world, especially in eastern Asia and Africa. Unfortunately, it is not sensitive to chemotherapy or radiotherapy. In addition, increasing evidence indicates that, similar to breast tissue, the liver is a hormone-responsive organ. HCC could therefore be an estrogen-dependent cancer. The importance of sex hormone receptors, such as estrogen receptor (ER), androgen receptor (AR) and progesterone receptor (PR) play important roles in the control of liver cell proliferation.MicroRNAs(miRNAs) are 21-23 nt long noncoding RNA sequences that are involved in various biological processes,including cell proliferation, cell death, stress resistance, and tumorigenesis.Recent studies indicate that miRNAs may play a role in several cancers. Altered miRNA levels can result in aberrant expression of gene products that may contribute to cancer biology, which suggests that expression profiling of miRNAs may significantly contribute to cancer development. Furthermore, it has also been shown that miRNA expression patterns have relevance to the biological and clinical behavior of human cancers.These and other data demonstrate that miRNAs play a substantial role in the pathogenesis of cancers, and miRNA is a novel targeting approach for cancer therapy.A recent study clearly demonstrated that miR-26a is a tumor suppressor that is reduced in hepatocellular carcinoma. In an MYC-inducible model of liver cancer, animals treated systemically with miR-26a (or with control microRNA) using adeno-associated virus for delivery shown significant tumor regression, indicating that the reintroduction of miR-26a may be an effective strategy to treat cancer. However, adeno-associated virus and EF1αpromoter lack of tumor-specificity, which will cause immune response and side effects.Tumor-specific promoters have shown great potential for the delivery of exogenous genes to specifically targeted tissues. HTERT and hAFP promoters have recently been reported to be effective in this capacity. However, the expression of genes regulated by a single tumor-specific promoter is much lower than that of genes regulated by other non-tumor-specific strong promoters.Specific expression of a microRNA (miRNA) regulated by tumor-specific promoters and a combination of the regulatory regions of hTERT and hAFP promoters has not been reported and mechanism of mir-26a to inhibit cancer were not fully understood. In this study, we aimed to answer the following questions. 1. Constructe the vector to drive miR-26a expression regulated by a hAFP-TERT dual promoter 2. Whether the hAFP-TERT dual promoter was tumor-specific and able to efficiently control miR-26a expression in liver cancer cells. 3. Whether this new plasmid overexpression miR-26a could suppress human cancer cell growth in vitro and in vivo. 4. To find new target gene of miR-26a and explore its role in suppressing human cancerOur data show that miR-26a expression driven by a hAFP-TERT dual promoter was tumor-specific and decreased the viability of tumor cells by regulating ERα, progesterone receptor (PR) and P53 except for cyclin D2 or cyclin E2 in vitro and in vivo. Our data also show that estradiol (E2) promotes the growth of liver cancer cells similar to breast cancer cells partly via the E2-ERαpathway and that miR-26a significantly down regulates ERαand prevents the stimulation of hepatoma cell growth by E2. These data suggest that ERα, which is regulated by miR-26a, is important for liver tumor cell growth. Moreover, hAFP-TERT dual promoter mediated miR-26a expression could specifically exert potential antitumor activity and provide a novel targeting approach for cancer therapy. |
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