Micro-RNAs miR-29a and miR-330-5p function as tumor suppressors by targeting the MUC1 mucin in pancreatic cancer cells

Abstract

MUC1 is an oncogenic mucin overexpressed in several epithelial cancers, including pancreatic ductal adenocarcinoma, and is considered as a potent target for cancer therapy. To control cancer progression, miRNAs became very recently, major targets and tools to inhibit oncogene expression. Inhibiting MUC1 using miRNAs appears thus as an attractive strategy to reduce cancer progression. However, potent miRNAs and associated mechanisms regulating MUC1 expression remain to be identified. To this aim, we undertook to study MUC1 regulation by miRNAs in pancreatic cancer cells and identify those with tumor suppressive activity. MiRNAs potentially targeting the 3'-UTR, the coding region, or the 5'-UTR of MUC1 were selected using an in silico approach. Our in vitro and in vivo experiments indicate that miR-29a and miR-330-5p are strong inhibitors of MUC1 expression in pancreatic cancer cells through direct binding to MUC1 3'-UTR. MUC1 regulation by the other selected miRNAs (miR-183, miR-200a, miR-876-3p and miR-939) was found to be indirect. MiR-29a and miR-330-5p are also deregulated in human pancreatic cancer cell lines and tissues and in pancreatic tissues of Kras(G12D) mice. In vitro, miR-29a and miR-330-5p inhibit cell proliferation, cell migration, cell invasion and sensitize pancreatic cancer cells to gemcitabine. In vivo intra-tumoral injection of these two miRNAs in xenografted pancreatic tumors led to reduced tumor growth. Altogether, we have identified miR-29a and miR-330-5p as two new tumor suppressive miRNAs that inhibit the expression of MUC1 oncogenic mucin in pancreatic cancer cells.

MicroRNA-29a functions as a potential tumor suppressor through directly targeting CDC42 in non-small cell lung cancer

“…In renal cell carcinoma, miR-29a expression was decreased, and functioned as a cell migration and invasion suppressor by targeting lysine oxidase homolog 2 (34). Tréhoux et al (35) demonstrated that miR-29a suppressed cell proliferation, migration and invasion, and sensitized cells to gemcitabine by directly targeting mucin 1 in pancreatic cancer. In gastric cancer, enforced expression of miR-29a significantly reduced cell migration and invasion ability via blockade of roundabout guidance receptor 1 (29).…”

Increased Expression of miR-29a and Its Prognostic Significance in Patients with Cholangiocarcinoma

“…One such miRNA, miR-29a, has been found to be deregulated in some human cancers. Downregulated expression of miR-29a has been investigated in gastric cancer, prostate cancer, and pancreatic carcinoma [40][41][42], while upregulated miR-29a expression has been found in glioma, breast cancer, acute myeloid leukemia, and nasopharyngeal carcinoma [43][44][45]. All these studies demonstrated that dysregulated miR-29a might act as a tumor suppressor or oncogene in different kinds of human cancer.…”

Chemoresistance in pancreatic cancer: Emerging concepts

“…Incidentally, miR-33a was also reported to be downregulated in gemcitabine-resistant cells (44). miR-29a and miR-330-5p have been revealed to serve as tumor suppressors by downregulating MUC1 expression and sensitizing pancreatic cancer cells to gemcitabine (46). Another study demonstrated that miR-21 overexpression results in an increased sensitivity to gemcitabine via a decrease in the expression levels of the p85α subunit of phosphatidylinositol-4,5-biphostphate 3-kinase (47).…”

“…miRs regulate the gene expression in the majority of biological processes in the cell, and therefore have been hypothesized to serve an important role in the chemoresistance to standard treatment regimens in pancreatic cancer. Numerous studies demonstrated that miRs are differentially expressed in a variety of types of cancer (44)(45)(46)(47)(48)(49)(50). A study examining the miR profile of gemcitabine-sensitive and resistant pancreatic cancer cell lines reported the presence of 33 differentially regulated miRs (44).…”