MicroRNA-mediated upregulation of integrin-linked kinase promotes Src-induced tumor progression

Abstract

The tyrosine kinase c-Src is upregulated in various human cancers; however, the molecular mechanisms underlying c-Src-mediated tumor progression remain unclear. Here we show that downregulation of microRNA (miR)-542-3p is tightly associated with tumor progression via c-Src-related oncogenic pathways. In c-Src-transformed fibroblasts and human cancer cells that overexpress c-Src, miR-542-3p is substantially downregulated, and the ectopic expression of miR-542-3p suppresses tumor growth. We identified the integrin-linked kinase (ILK) as a conserved target of miR-542-3p. ILK upregulation promotes cell adhesion and invasion by activating the integrin-focal adhesion kinase (FAK)/c-Src pathway, and can also contribute to tumor growth via the AKT and glycogen synthase kinase 3b pathways. MiR-542-3p expression is downregulated by the activation of c-Src-related signaling molecules, including epidermal growth factor receptor, K-Ras and Ras/ Raf/mitogen-activated protein kinase/extracellular signalregulated kinase. In human colon cancer tissues, downregulation of miR-542-3p is significantly correlated with the upregulation of c-Src and ILK. Our results suggest that the novel c-Src-miR-542-3p-ILK-FAK circuit plays a crucial role in controlling tumor progression.

MicroRNA-542-3p Suppresses Tumor Cell Invasion via Targeting AKT Pathway in Human Astrocytoma

“…Consistent with our results, miR-542-3p has been reported to be down-regulated in colon cancer cell lines and to inhibit colon cancer cell proliferation and invasion via targeting ILK (44). Moreover, overexpression of miR-542-3p induces G 1 and G 2 /M arrest in multiple cancer cell lines, including lung cancer, breast cancer, and cervical cancer (24).…”

Decreased miR-340 Expression in Bone Marrow Is Associated with Liver Metastasis of Colorectal Cancer

“…In vitro studies showed that addition of pre-miR-340 or pre-miR-542-3p led to inhibition of cell growth of colon cancer cells, suggesting these miRNAs to be anti-oncomirs, as has been reported in other cancer types: miR-340 in breast cancer (24) and colorectal (43), and miR-542-3p in colon (27) and lung cancer (26). Furthermore, pre-miR-340 and pre-miR-542-3p suppressed the target genes: c-Met (24) and MITF (25) for miR-340, and Survivin (26) for miR-542-3p.…”

“…Five miRNAs were decreased and the other five were increased in BM4 cells from the patients with colorectal cancer with liver metastasis compared with in those without metastasis. Table 1 presents information about each miRNA, including the target molecule and whether it is an anti-oncomir or oncomir according to the available literature (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). All data from the miRNA array are shown in Supplementary microarray results.…”

Src Points the Way to Biomarkers and Chemotherapeutic Targets

“…140 Furthermore, Src downregulates the expression of oncomirs, including miR-99a and miR-542-3p, to promote tumor progression. 143,144 Further elucidation of miRNA pathways should elucidate their clinical relevance and use as biomarkers and potential chemotherapeutic targets.…”