Abstract
Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. In Saudi Arabia, colorectal cancer is more aggressive and presents at younger age, warranting new treatment strategies. Role of TGFβ/Smad4 signaling pathway in initiation and progression of colorectal cancer is well documented. This study examined the role of TGFβ/Smad4 signaling pathway in a large cohort of Saudi patients with colorectal cancer, 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 subgroup of aggressive colorectal cancer to be an independent marker for poor prognosis. Functional studies using colorectal cancer 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 colorectal cancer 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 patients with colorectal cancer. Functional study results indicate that TGFβ induces Smad4-dependent EMT followed by apoptosis in colorectal cancer cells.
Highlights
Colorectal cancer is one of the most common malignancy and the second leading cause of death by cancer in Western populations [1]
We evaluated the Smad4 protein expression in more than 1,000 Saudi patients with colorectal cancer, as well as genomic mutation and gene deletion
We show that low levels of Smad4 protein can identify a subset of patients with Dukes' C colorectal cancer who have a high probability of recurrence following potentially curative surgery and 5-FU–based adjuvant chemotherapy
Summary
Colorectal cancer is one of the most common malignancy and the second leading cause of death by cancer in Western populations [1]. There have been remarkable changes in the rate of colorectal cancer incidence and mortality over the past few decades in other ethnic population [2]. In Saudi Arabia, colorectal cancer presents the number one cancer affecting Saudi males and the third most common among females [3]. Few studies have shown that colorectal cancer affecting Saudi population tends to be more aggressive and present with advanced stage [4, 5]. Colorectal cancer has a complex pathogenesis involving multiple genetic and epigenetic alterations caused by somatic mutations that lead to uncontrolled tumor cell proliferation, invasiveness, and distant metastatic potential [6, 7].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
