Abstract
Transmembrane-4-L-six-family-1(TM4SF1), a four-transmembrane L6 family member, is highly expressed in various pancreatic cancer cell lines and promotes cancer cells metastasis. However, the TM4SF1-associated signaling network in metastasis remains unknown. In the present study, we found that TM4SF1 affected the formation and function of invadopodia. Silencing of TM4SF1 reduced the expression of DDR1 significantly in PANC-1 and AsPC-1 cells. Through double fluorescence immuno-staining and Co-immunoprecipitation, we also found that TM4SF1 colocalized with DDR1 and had an interaction with DDR1. In addition, upregulating the expression of DDR1 rescued the inhibitory effects of cell migration and invasion, the expression of MMP2 and MMP9 and the formation and function of invadopodia when TM4SF1 silenced. In pancreatic cancer tissues, qRT-PCR and scatter plots analysis further determined that TM4SF1 had a correlation with DDR1. Collectively, our study provides a novel regulatory pathway involving TM4SF1, DDR1, MMP2 and MMP9, which promotes the formation and function of invadopodia to support cell migration and invasion in pancreatic cancer.
Highlights
Pancreatic cancer is the fifth most common cause of cancer-related deaths in the United States, for which 5-year survival rate is 7%1
The results suggested that over 40% of PANC-1 siCtrl cells contained invadopodia compared with approximately 11% of PANC-1 siTM4SF1 cells (Fig. 1C)
Through Small interfering RNA (siRNA) and plasmids transfection, we found that silencing Transmembrane 4 L six family member 1 (TM4SF1) decreased the expression of Discoidin Domain Receptor 1 (DDR1), matrix metallopeptidase 2 (MMP2) and matrix metallopeptidase 9 (MMP9), whereas up-regulation of DDR1 expression rescued the decreased expression of MMP2 and MMP9 (Figs 3A and 4A). pcDNA3.1-DDR1 plasmids were transfected in PANC-1/siTM4SF1 cells to overexpress DDR1 to determine whether TM4SF1 had an interaction with DDR1 to affect the formation and function of invadopodia
Summary
Pancreatic cancer is the fifth most common cause of cancer-related deaths in the United States, for which 5-year survival rate is 7%1. In PANC-1 and AsPC-1, TM4SF1 mediated the expression and activities of matrix metallopeptidase 2 (MMP2) and matrix metallopeptidase 9 (MMP9) which were the major regulators of extracellular matrix (ECM) degradation to increase the cells migration and invasion. TM4SF1 was necessary for the formation of the special projections that termed nanopodia[10] These studies suggested that TM4SF1 played an essential role on the tumorigenesis and progression of pancreatic cancer. The expression of DDR1 is significantly higher and is related with poor prognosis in patients by the retrospective study[15]. Both TM4SF1 and DDR1 are overexpressed in pancreatic cancer and related with metastasis development. We hypothesized that TM4SF1 might collaborate with DDR1 involved in the formation of invadopodia which had the ability to degrade ECM to regulate pancreatic cancer metastasis
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