Abnormal accumulation and activation of receptor tyrosine kinase Ron (recepteur d'origine nantais) has been demonstrated in a variety of primary human cancers. We show that RNA interference-mediated knockdown of Ron kinase in a highly tumorigenic colon cancer cell line led to reduced proliferation as compared with the control cells. Decreased Ron expression sensitized HCT116 cells to growth factor deprivation stress-induced apoptosis as reflected by increased DNA fragmentation and caspase 3 activation. In addition, cell motility was decreased in Ron knockdown cells as measured by wound healing assays and transwell assays. HCT116 cells are heterozygous for gain of function mutant PIK3CA H1047R. Analysis of signaling proteins that are affected by Ron knockdown revealed that phosphatidylinositol 3-kinase (PI3K) activity of the mutant PI3K as well as AKT phosphorylation was substantially reduced in the Ron knockdown cells compared with the control cells. Moreover, we demonstrated in vivo that knockdown of Ron expression significantly reduced lung metastasis as compared with the control cells in the orthotopic models. In summary, our results demonstrate that Ron plays an essential role in maintaining malignant phenotypes of colon cancer cells through regulating mutant PI3K activity. Therefore, targeting Ron kinase could be a potential strategy for colon cancer treatment, especially in patients bearing gain of function mutant PI3K activity.The receptor tyrosine kinase Ron (recepteur d'origine nantais) belongs to the Met proto-oncogene family (1, 2). Mature Ron is a 180-kDa heterodimer composed of a 40-kDa extracellular ␣-chain and a 150-kDa transmembrane -chain with tyrosine kinase activity (2). Macrophage-stimulating protein is the only ligand that has been identified for Ron (3, 4). Upon ligand binding, Ron dimerizes, becomes autophosphorylated, and transduces a variety of signals that regulate different downstream pathways including Ras/mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), 3 c-Jun N-terminal kinase (JNK), -catenin, and nuclear factor-B (5-12). Ron can be activated through ligand-dependent or -independent mechanisms (3,13,14), which lead to responses important for tumorigenesis and metastasis, including cell scattering, proliferation, motility, and survival (15,16).Ron is normally expressed at relatively low levels in cells of epithelial origin (4). Recent studies have shown that Ron is overexpressed in 47% of breast tumor tissues as compared with benign epithelium and that elevated Ron expression was strongly associated with invasive activity by tumors (17). In addition, Ron is moderately expressed in normal colorectal mucosa, but is significantly increased in the majority of primary human colorectal adenocarcinoma samples (18). Ron overexpression has also been demonstrated in head and neck tumors (19). Furthermore, splice variants of Ron have been identified in human colon cancer. These variants were found to confer constitutive Ron activity, transformation, and tumorige...
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BackgroundTGFβ signaling has typically been associated with suppression of tumor initiation while the role it plays in metastasis is generally associated with progression of malignancy. However, we present evidence here for an anti-metastatic role of TGFβ signaling.MethodsTo test the importance of TGFβ signaling to cell survival and metastasis we compared human colon carcinoma cell lines that are either non-tumorigenic with TGFβ response (FET), or tumorigenic with TGFβ response (FETα) or tumorigenic with abrogated TGFβ response via introduction of dominant negative TGFβRII (FETα/DN) and their ability to metastasize. Metastatic competency was assessed by orthotopic transplantation. Metastatic colony formation was assessed histologically and by imaging.ResultsAbrogation of TGFβ signaling through introduction of a dominant negative TGFβ receptor II (TGFβRII) in non-metastatic FETα human colon cancer cells permits metastasis to distal organs, but importantly does not reduce invasive behavior at the primary site. Loss of TGFβ signaling in FETα-DN cells generated enhanced cell survival capabilities in response to cellular stress in vitro. We show that enhanced cellular survival is associated with increased AKT phosphorylation and cytoplasmic expression of inhibitor of apoptosis (IAP) family members (survivin and XIAP) that elicit a cytoprotective effect through inhibition of caspases in response to stress. To confirm that TGFβ signaling is a metastasis suppressor, we rescued TGFβ signaling in CBS metastatic colon cancer cells that had lost TGFβ receptor expression due to epigenetic repression. Restoration of TGFβ signaling resulted in the inhibition of metastatic colony formation in distal organs by these cells. These results indicate that TGFβ signaling has an important role in the suppression of metastatic potential in tumors that have already progressed to the stage of an invasive carcinoma.ConclusionsThe observations presented here indicate a metastasis suppressor role for TGFβ signaling in human colon cancer cells. This raises the concern that therapies targeting inhibition of TGFβ signaling may be imprudent in some patient populations with residual TGFβ tumor suppressor activity.
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