miR-194 suppresses metastasis of non-small cell lung cancer through regulating expression of BMP1 and p27kip1

Abstract

MicroRNAs (miRNAs) are increasingly implicated in regulating tumor malignance through their capacity to coordinately repress expression of tumor-related genes. Here, we show that overexpression of miR-194 in lung cancer cell lines, results in suppressing metastasis of lung cancer cells, while inhibiting its expression through 'miRNA sponge' promotes the cancer cells to metastasize. miR-194 expression is also found to be in strongly negative association with metastasis in clinical specimens of non-small cell lung cancer. We demonstrate that miR-194 directly targets both BMP1 and p27(kip1). The resulting downregulation of BMP1 leads to suppression of TGFβ activity and, thus, to downregulation of the expression of key oncogenic genes (matrix metalloproteinases MMP2 and MMP9). This leads, in turn, to decreased tumor invasion. In addition, the miRNA-194-induced suppression of p27(kip1) activates the RhoA pathway, producing enhanced development of actin stress fibers and impaired migration of cancer cells. These findings reveal two structurally independent but functionally linked branches of the regulatory and signaling pathway that together provide a bridge between the metastasis-depressing miRNA and the key genes that govern the malignancy of lung cancers.

BMP-1/tolloid-like proteinases synchronize matrix assembly with growth factor activation to promote morphogenesis and tissue remodeling

“…In a similar vein, both BMP-1 and PCPE-1 were found to be among a list of desmoplastic markers secreted by cancer associated fibroblasts in colorectal cancer [105]. Furthermore, microRNA miR-194 downregulation of Bmp1 expression was found to reduce lung metastasis, apparently by reducing levels of TGF-β activation and consequent expression of MMP-2/-9 [106]. A key component of metastasis is angiogenesis.…”

MiR-194, commonly repressed in colorectal cancer, suppresses tumor growth by regulating the MAP4K4/c-Jun/MDM2 signaling pathway

“…8,9 Recent data have shown that miR-194 plays an important part in tumorigenesis. For example, miR-194 was found to act as a tumor suppressor in gastric cancer, 10 endometrial cancer, 11 renal cell carcinoma, 12 lung cancer, 13 and breast cancer, 14 while upregulated as an oncogene in pancreatic cancer. 15 In CRC, miR-194 has been reported to be downregulated in colon tissues 16 and can predict adenoma recurrence.…”

Original Research: miR-194 inhibits proliferation and invasion and promotes apoptosis by targeting KDM5B in esophageal squamous cell carcinoma cells

“…For example, some studies showed that it is downregulated and functions as a tumor suppressor in some malignant tumors such as non-small cell lung cancer and endometrial cancer. 10,11 But some studies demonstrated that it is up-regulated and acts as an oncogene in EAC, prostate cancer, etc.…”