Enforced Expression of miR-101 Inhibits Prostate Cancer Cell Growth by Modulating the COX-2 Pathway In Vivo

Abstract

It is commonly agreed that there is an association of chronic inflammation with tumorigenesis. COX-2, a key regulator of inflammation-producing prostaglandins, promotes cell proliferation and growth; thus, overexpression of COX-2 is often found in tumor tissues. Therefore, a better understanding of the regulatory mechanism(s) of COX-2 could lead to novel targeted cancer therapies. In this study, we investigated the mechanism of microRNA-101 (miR-101)-regulated COX-2 expression and the therapeutic potential of exogenous miR-101 for COX-2-associated cancer. A stably expressing exogenous miR-101 prostate cancer cell line (BPH1CmiR101) was generated by using lentiviral transduction as a tool for in vitro and in vivo studies. We found that miR-101 inhibited COX-2 posttranscriptional expression by directly binding to the 3′-untranslated region (3′-UTR) of COX-2 mRNA. The regulatory function of miR-101 was also confirmed by using antisense DNA. As a result, exogenous miR-101 is able to effectively suppress the growth of cultured prostate cancer cells and prostate tumor xenografts. The average tumor weight was significantly lower in the BPH1CmiR101 group (0.22 g) than the BPH1Cvec group (0.46 g). Expression levels of the cell growth regulators, such as cyclin proteins, PCNA (proliferating cell nuclear antigen), EGFR (epidermal growth factor receptor), were also studied. In conclusion, COX-2 is a direct target in miR-101 regulation of posttranscription. Exogenous miR-101 suppresses the proliferation and growth of prostate cancer cells in vitro and in vivo. These data suggest that exogenous miR-101 may provide a new cancer therapy by directly inhibiting COX-2 expression.

Esophageal squamous cell carcinoma cell proliferation induced by exposure to low concentration of cigarette smoke extract is mediated via targeting miR-101-3p/COX-2 pathway

“…To unravel miRNA and its function may provide better understanding of how environmental factors contribute to cancer initiation and development. miR-101-3p has been reported downregulated in many types of cancers, including ESCC (13), prostate (14) and colorectal cancer (15). Through post-transcriptional inhibition of targets, such as cyclooxygenase-2 (COX-2/PTGS2) (16), EZh2/ENX-1 (13), Mcl-1(17), mTOR (18), miR-101-3p could suppress cancer cell proliferation, migration and invasion.…”

“…As miR-101 was reported to inhibit COX-2 post-transcriptional expression by binding to the 3'-UTR of COX-2 mRNA in prostate and colon cancer cells (14,15), to verify whether COX-2 is a direct target of miR-101-3p in esophageal cancer cell lines, COX-2 3'-UTR containing the miR-101 binding sites (WT), and binding site mutant (Fig. 3A) were cloned downstream of the luciferase open reading frame to obtain constructs for luciferase activity assay.…”

MicroRNA-101 Inhibits Cell Proliferation, Invasion, and Promotes Apoptosis by Regulating Cyclooxygenase-2 in Hela Cervical Carcinoma Cells

“…As an aspect of the relationship with the microRNA-101, the prediction based on PicTar and TargetScan DNA analysis software suggest that COX-2 could be one direct target for miR-101 because miR-101 has a seed region, which is able to bind to the COX-2 mRNA 3-UTR. Such as miR-101 and COX-2 can control the development of mammary gland (Tanaka et al, 2009), colon cancer (Strillacci et al 2009) and prostate cancer (Hao et al, 2011). In recent years, studies have found that some cancer cells ,which have a high-expression of COX-2, their ability of the proliferation and metastasis have also been highly focused.…”

Downregulated microRNA-26a modulates prostate cancer cell proliferation and apoptosis by targeting COX-2

“…Wu et al (9) showed that miR-146a enhances Helicobacter pylori-induced cell apoptosis in human gastric cancer epithelial cells by targeting COX-2. Hao et al (22) demonstrated that enforced expression of miR-101 inhibits prostate cancer cell growth by modulating the COX-2 pathway. miR-16 has also been identified as a potential tumor regulator by targeting COX-2 (23).…”