Role Of Activin C In Decorin Deficiency Induced Colorectal Cancer Development And Progression

Colorectal cancer is still the third most commonly diagnosed cancer worldwise,according to World Cancer Report 2014.In China,the incidence of colorectal cancer tends to increase every year,but the therapy is still poor.Decorin is a member of the small leucine-rich proteoglycan family.As a tumor suppressor,decorin could interact with some growth factors,cytokines or cell membrane receptors to regulate multiple signaling pathways,thereby inhibiting tumor cell proliferation,metastasis and angiogenesis,or inducing apoptosis and autophagy.In mechanism,decorin partnering with EGFR or ErbB2/4 inhibits tumor cell proliferation or induces apoptosis,partnering with TGF-? inhibits angiogenesis,partnering with Met or E-cadherin inhibits metastasis and partnering with VEGFR induces autophagy.Therefore,decorin plays an important role in reducing tomor development and progression.Activin C is a member of the transforming growth factor-?(TGF-?)superfamily.To date,the biological role of activin C was less investigated and mainly concentrated in liver due to its late discovery.Some investigators have shown that activin C inhibits regenerative DNA synthesis of hepatic cells and liver regeneration.In recent years,the various biological activities of activin C have been reported in other tissues.However,there is no investigation about activin C in colorectal cancer cells.Our previous study has shown that genetic deletion of the decorin gene is sufficient to cause intestinal tumor formation in mice.Overexpression of decorin inhibits the growth and migration of colorectal cancer cells.Herein,as a continued study,we will investigate the new mechanism of decorin-mediated inhibition of colorectal cancer.Base on the facts that activins/smad and TGF-? signaling pathway both are mutation in colorectal cancer cells,while decorin could inhibits TGF-?1 to increase cell proliferation and angiogenesis.Accordingly,we investigated the interaction between decorin and activin C in vivo and in vitro,and the biological functions and the mechanism of activin C in colorectal cancer.As the results:(1)Activin C was negatively regulated by decorinWestern blot assay shown that loss of decorin led to the increases of activin C in mice.Contrary,restored decorin could decrease the level of activin C by accelerating its degradation in HCT116 and HEK293 cells.Taking together,activin C wasnegatively regulated by decorin.(2)Activin C up-regulated AP-1 to promote proliferation,migration and invasion via MAPK pathway in HCT116 cellsMTT,western blot,wound healing and transwell assay shown that both recombinant activin C and overexpression of activin C up-regulated CDK4 and Cyclin D1,promote cell motility and metastasis in HCT116 cells,while these effects were attenuated by si-RNA targeting activin C,which suggested activin C promoted cell proliferation,migration and invasion in HCT116 cells.In mechanism study,we found that activin C up-regulatd AP-1 via ERK/c-Fos and JNK/c-Jun pathway but not activins/smad signaling pathway to affect HCT116 cells.(3)Activin C was partially involved in decorin-mediated inhibiting ERK/c-Fos and JNK/c-Jun pathwayCombined overexpression of decorin and si-RNA targeting activin C,we found that restored decorin highly increased caveolin-1 and still decrease the level of AP-1,although si-RNA targeting activin C was performed,which suggested decorin inhibited ERK/c-Fos and JNK/c-Jun pathway without depending on activin C but associated with caveolin-1.(4)Decorin interacts with activin CCo-IP and confocal fluorescence image demonstrated that decorin directly interacted with activin C in colorectal cancer cells.In summary,in the present study we provided the first evidence that activin C could promote colorectal cancer cell proliferation,migration and invasion by activating AP-1 via ERK/c-Fos and JNK/c-Jun pathway.In addition,decorin directly interacted with activin C and accelerated its degradation.Moreover,activin C was partially involved in decorin-mediated inhibiting ERK/c-Fos and JNK/c-Jun pathway,which was associated with caveolin-1.Thereby,decorin-mediated colorectal cancer inhibition is associated with activin C.