A functional role for Smad7 in sustaining colon cancer cell growth and survival

Abstract

Initially identified as an inhibitor of transforming growth factor (TGF)-β mainly owing to its ability to bind TGF-β receptor type I and abrogate TGF-β-driven signaling, Smad7 can interact with additional intracellular proteins and regulate TGF-β-independent pathways, thus having a key role in the control of neoplastic processes in various organs. Genome-wide association studies have shown that common alleles of Smad7 influence the risk of colorectal cancer (CRC), even though the contribution of Smad7 in colon carcinogenesis is not fully understood. In this study, we assessed the expression and role of Smad7 in human and mouse models of sporadic CRC. We document a significant increase of Smad7 in human CRC relative to the surrounding nontumor tissues and show that silencing of Smad7 inhibits the growth of CRC cell lines both in vitro and in vivo after transplantation into immunodeficient mice. Knockdown of Smad7 results in enhanced phosphorylation of the cyclin-dependent kinase (CDK)2, accumulation of CRC cells in S phase and enhanced cell death. Smad7-deficient CRC cells have lower levels of CDC25A, a phosphatase that dephosphorylates CDK2, and hyperphosphorylated eukaryotic initiation factor 2 (eIF2)α, a negative regulator of CDC25 protein translation. Consistently, knockdown of Smad7 associates with inactivation of eIF2α, lower CDC25A expression and diminished fraction of proliferating cells in human CRC explants, and reduces the number of intestinal tumors in Apcmin/+ mice. Altogether, these data support a role for Smad7 in sustaining colon tumorigenesis.

microRNA-497 Modulates Breast Cancer Cell Proliferation, Invasion, and Survival by Targeting SMAD7

“…In our in vivo study, the SMAD7 could cause cell cycle S arrest, which was coinciding to the phenomenon reported by C Stolfi et al (2014). In the same article, CDC25A was identified as a specific downstream protein of SMAD7, leading to dephosphorylation of CDK2 and inhibition of CDK2 cyclin complex activity (Stolfi et al, 2014). Furthermore, in Cox regression analysis, the miR-497 low expression displayed a hazardous tend for BC survival ( p = 0.061), which meant miR-497 could not stand for an independent marker for BC survival in our study (Table 3).…”

“…Combined with the relationship between miR-497 and SMAD7 in tissues, we suggested the miR-497 could also influence the BC survival by regulating SMAD7. In our in vivo study, the SMAD7 could cause cell cycle S arrest, which was coinciding to the phenomenon reported by C Stolfi et al (2014). In the same article, CDC25A was identified as a specific downstream protein of SMAD7, leading to dephosphorylation of CDK2 and inhibition of CDK2 cyclin complex activity (Stolfi et al, 2014).…”

Esophageal cancer in a family with hamartomatous tumors and germline PTEN frameshift and SMAD7 missense mutations

“…The TGF-β pathway has a complex relationship to cancer development, serving as both a pro- and anti-proliferative and apoptotic signal in different cell types and contexts,[32,34] and recent research suggests an important role for SMAD7 in cancer susceptibility, progression, and evasion of immune surveillance. [32,34–38] Loss of SMAD7 protein causes decreased colorectal cancer cell growth in vitro , but in vivo also decreases the ability of tumor infiltrating lymphocytes to induce cancer cell apoptosis, thereby promoting metastasis.…”

“…[32,34–38] Loss of SMAD7 protein causes decreased colorectal cancer cell growth in vitro , but in vivo also decreases the ability of tumor infiltrating lymphocytes to induce cancer cell apoptosis, thereby promoting metastasis. [32,34] Smad7 knockout increases rates of hepatocellular carcinoma (HCC) formation after diethylnitrosamine injection in mice,[38] and negative SMAD7 staining by IHC correlates with worse survival in human esophageal squamous and pancreatic cancers. [39,40] IHC results in Patient III-2 esophageal tumor specimen demonstrate intact levels of SMAD7 protein expression, however, whether the function of this protein is affected by the G39R mutation remains unknown.…”

Multiple Functional Risk Variants in a SMAD7 Enhancer Implicate a Colorectal Cancer Risk Haplotype

“…SMAD7 overexpression has been seen in some CRC cells, and reduction of SMAD7 expression using anti-sense RNA leads to decreased proliferation in the HCT-116 CRC cell line and human CRC neoplastic explants, and reduced tumorigenesis in the APC min/- mouse [7].…”