FMNL2 enhances invasion of colorectal carcinoma by inducing epithelial-mesenchymal transition.
FMNL2 is a member of diaphanous-related formins that control actin-dependent processes such as cell motility and invasion. Its overexpression in metastatic cell lines and tissues of colorectal carcinoma has been associated with aggressive tumor development in our previous study. But its specific role in cancer is largely unknown. Here we report that FMNL2 is involved in epithelial-mesenchymal transition (EMT) maintenance in human colorectal carcinoma cells. A positive correlation between FMNL2 and vimentin expression and an inverse correlation between FMNL2 and E-cadherin expression were found in colorectal carcinoma cell lines and cancer tissues. Specific knockdown of FMNL2 led to an epithelial-state transition, confirmed by the cobblestone-like phenotype, upregulation of E-cadherin, α-catenin, and γ-catenin, and downregulation of vimentin, snail, slug. Loss of FMNL2 expression lowered the ability of TGF-β to induce cell invasion and EMT, as shown by morphology and the expression levels. Upregulation of vimentin, slug, snail, downregulation of E-cadherin and activation of receptor-Smad3 phosphorylation were observed in M5 and MDCK cells induced by TGF-β, whereas altered expression of these markers was not obvious in FMNL2-depleting M5 cells. High levels of activation of p-MAPK and p-MEK, but not p-PI3K and p-AKT, were observed in SW480/FMNL2+ cells compared with control cells. Treatment with U0126 could abrogate the activation of p-MAPK and p-MEK, whereas LY294002 treatment had no effect on the PI3K/AKT pathway. In conclusion, these findings identify a novel EMT and tumor promoting function for FMNL2, which is involved in TGF-β-induced EMT and colorectal carcinoma cell invasion via Smad3 effectors, or in collaboration with MAPK/MEK pathway.
Department of Pathology, School of Basic Medical Sciences, Southern Medical University, 1838, North Guangzhou Street, Baiyun Region, Guangzhou 510515, Guangdong Province, People's Republic of China.
Yufa
Y
Li
Xiling
X
Zhu
Yuanfeng
Y
Zeng
Jianmei
J
Wang
Xiaojing
X
Zhang
Yan-qing
YQ
Ding
Li
L
Liang
D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D000080865:Formins; D055785:Gene Knockdown Techniques; D019073:HT29 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation; D014746:Vimentin / Q000235:genetics / Q000378:metabolism
D015820:Cadherins; C476208:FMNL2 protein, human; D000080865:Formins; D011506:Proteins; D016212:Transforming Growth Factor beta; D014746:Vimentin; D020929:Mitogen-Activated Protein Kinase Kinases