Repository series · ncbi-prjeb32337

TGFβ Induced SMAD4 Dependent Apoptosis Proceeded by EMT in CRC​

Colorectal cancer (CRC) is one of the leading cause of cancer-related deaths Worldwide. In Saudi Arabia, CRC is more aggressive and presents at younger age, warranting new treatment strategies. Role of TGFβ/Smad4 signaling pathway in initiation and progression of CRC is well documented. Current study examined the role of TGFβ/Smad4 signaling pathway in a large cohort of Saudi CRC, followed by in vitro analysis to dissect the dual role of TGFβ on inducing epithelial to mesenchymal transition (EMT) and apoptosis. Our study demonstrated high frequency of Smad4 alterations with low expression of Smad4 protein identifying a sub-group of aggressive CRC to be an independent marker for poor prognosis. Functional studies using CRC cells show that TGFβ induces Smad4 dependent EMT followed by apoptosis. Induction of mesenchymal transcriptional factors, Snail1 and Zeb1 was essential for TGFβ-induced apoptosis. Our results indicate that KLF5 acts as an oncogene in CRC cells regardless of Smad4 expression and inhibition of KLF5 is requisite for TGFβ-induced apoptosis. Furthermore, TGFβ/Smad4 signal inhibits the transcription of KLF5 that in turn switches Sox4 from tumor promoter to suppressor. A high incidence of Smad4 alterations were found in the Saudi CRC patients. Functional study results indicate that TGFβ induces Smad4 dependent EMT followed by apoptosis in CRC cells.