SMAD1 Gene And Risk Of Colorectal Cancer In The Bangladesh

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The gradual growth of genetic and epigenetic alterations in colon epithelium is the main culprit behind the commencement and progression of colorectal cancer development. The lists of these alterations are long and persist to grow. On the other hand, only a small number of genes thought to be contributing to the initiation of colorectal carcinogenesis (van den Brink and Offerhaus, 2007). For this reason, these genes and the signalling pathways to which they are the associate of are particularly fascinating to study. Several studies revealed that SMAD proteins are essential for TGF-β signal transduction in the majority of cell types. It is assumed that inactivating mutations in the SMAD genes interrupt the signal transduction pathway between the cell membrane receptors and the cell nucleus.

SMAD2 is a contender tumour suppressor as mutations in SMAD2 are particularly associated with sporadic colorectal carcinoma. SMAD2 mutation takes place in the early stages of cancer whereas SMAD4 mutations arise in advanced stage cancers (lymph node involvement and metastasis). Animal studies revealed that SMAD3 is another influential tumour suppressor for colonic epithelium since it demonstrated that inbred SMAD3 homozygous mutants build up colon adenocarcinoma in various stages.

Plentiful genome-wide association studies (GWAS) has been utilized to recognize genetic variation in the SMAD7 gene on 8q21 as being associated with CRC. Previous studies provide properly recorded evidence for the association of SMAD1 with advanced cancer stage and migration. The upregulation of SMAD1 in human colorectal specimens both in Caucasian and Asian population have been reported by several groups. A methodical research was conducted by Korchynskyi et al. (1999) where they observed the expression of SMAD proteins of all groups in the same specimen of human CRC of the Ukrainian populace. They observed upregulation of receptor-activated SMAD1 in a portion of the tumour cells. Their findings concluded that there are alterations in TGF-β signalling in colorectal carcinogenesis.

Ruan et al. (2015) and his team validated the finding of SMAD1 upregulation in tumours by collecting 542 human colorectal tumour specimens (stages I to IV) from the Chinese Han population. Although tumour patient samples expressed increased levels of SMAD1, normal mucosa samples expressed SMAD1 at low levels. At later stages, SMAD1 levels appeared to go down. These consequences point out those colorectal tumours tend to upregulate SMAD1 expression. Several genetic studies on human and mouse disclose that the BMP-SMAD pathway possesses a tumour suppressor function.

Kodach et al. (2007) and colleagues reported that they found downregulation of BMP-SMAD1 signalling in human colon cancer samples. They observed the nuclear pSMAD1, 5, 8 expressions and declared that even though the BMP pathway was inactivated in 80% of CRCs, it was active in adenomas. The selective loss of pSMAD1, 5, 8 nuclear staining in regions of high-grade dysplasia/carcinoma in situ inside adenomas recommended that loss of BMP signalling is a phenomenon associated with the development of adenomas to carcinomas. The same outcome concluded by Lorente-Trigos et al. (2010) and Kodach et al. (2008) that BMP-SMAD1 operates as a tumour suppressor upholding apoptosis in mature colonic epithelial cells, and thus increased tumorigenesis could take place due to perturbations in BMP signalling. Even though the above studies confirmed that BMP-SMAD1 pathway suppresses tumorigenesis, yet little is known about how BMP-SMAD1 suppresses tumour formation, why SMAD1 is upregulated in human CRC samples and the evident role of SMAD1 in CRC. Even though the above studies confirmed that BMP-SMAD1 pathway suppresses tumorigenesis, thus far little is known about how BMP-SMAD1 suppresses tumour formation, why SMAD1 is upregulated in human CRC samples and the evident role of SMAD1 in CRC.

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Chau et al. (2012) discovered one of the ways by which this puzzle could be solved; they branded SMAD1 as an added player in the DDR. SMAD1 leads to maximal p53 induction by activation through sequential BMPRIA-mediated SXS phosphorylation and Atm-mediated S239 phosphorylation. Why the dysfunction of BMP-SMAD1 signalling results in tumorigenesis is answered by the tie to the prominent Atm-p53 tumour suppression pathway. SMAD1 is found to be phosphorylated on S239 during oesophageal tumour progression since it is an element of the DDR. In addition, it is often mutated in gastric cancer samples and is activated in different tumour cell lines in response to radio- or chemotherapy drugs. As such, SMAD1 might be a goldmine for developing the anti-cancer drug.

An innovative aspect of the functional interaction between p53 and SMAD1 was uncovered by Ruan X et al. (2015). Their study demonstrated that SMAD1 is upregulated when p53 is mutated or expressed at low levels. By escalating p57Kip2 expression and enhancing Atm–Chk2 activation, it helps to restrain cell proliferation and oncogenesis. Therefore, SMAD1 elevation may act as a compensation for p53 mutation/loss. On the other hand, these findings further emphasize that SMAD1 suppresses tumorigenesis with both p53-dependent and p53- independent mechanisms.

Another original research conducted by Yang et al. (2017) provides evidence of the influence of SMAD1 in colorectal cancer. They stated that cell migration in colorectal cancer cells is promoted via induced expression of Ajuba and Snail, which is attributable to SMAD1. Clinically, the positive correlation between the level of SMAD1 and the levels of Ajuba in CRC specimens is found. This present work offers the first evidence of the regulatory network of SMAD1-Ajuba axis in CRC. Evidence for mutations affecting these proteins in CRCs is limited despite the role of SMAD1 as direct mediators of BMP signalling and binding partners for SMAD4.

To determine a more precise estimation of the relationship between SMAD1 and CRC, we undertook a case-control study in the Bangladeshi population, which included a total of 575 subjects (275 cases and 300 controls). Although scientists are shedding light on this area, there are still considerable challenges in elucidating the influence of genetic variation on the expression of SMAD1, such as resolving the multifarious functional consequences of perhaps quite delicate perturbations of the pathway at many points. In case of rs11100883 polymorphisms, the study revealed that individual carrying A/G heterozygous and A/A mutant homozygous alleles possess 1. 55 and 1. 86-fold increased risk of developing colorectal cancer compared to control group, respectively and although findings for A/G heterozygous are counted as statistically significant since p value is less than 0. 05. In addition, A/G + A/A genotype together also increased the risk of colorectal cancer development (adjusted OR = 1. 59) and the findings are statistically significant. T

he present study unveiled a significant association between the SMAD1 rs7661662 polymorphism and colorectal cancer risk in Bangladeshi population for the first time. Frequencies of A/G and G/G genotype were found to be 32. 23% and 1. 59% respectively. The current research data also exhibited that A/G genotype increased the risk of colorectal cancer by 1. 77-fold in comparison with A/A genotype. The percentage frequency of A/G genotype was higher in colorectal cancer patients than unaffected controls (37. 23% vs. 25%) depicting a significant increase in risk among SMAD1 AG allele carriers. Along with this, the combination of A/G + G/G genotype with an adjusted odds ratio of 1. 70 and a p-value of < 0. 01 also comprised a significant risk associated with colorectal cancer in the Bangladeshi population. Whereas the present study explained that SMAD1 mutations are bona fide contributors to the mutation burden in CRCs in Bangladeshi population, a case-control study conducted on the Caucasian population by Slattery et al. (2012) reported the opposite. They evaluated genetic variation in TGF-β signalling pathway components including SMAD1 (rs714195, rs6537355, rs2118438, rs1016792 and rs12505085) and risk of colon and rectal cancer. They didn’t find any variations in TGFb1, SMAD1, SMAD2, and SMAD4 were not linked to survival after diagnosis (colon and rectal cancer). Such a differential association could have arisen from differences in the socioeconomic surroundings, local dietary habits, and race.

Bevan and colleagues (1999) monitored for germline mutations of SMAD1 in 30 patients collected from the mixed population (UK, Israel, Australia, USA, and Japan) with JPS and without SMAD4 mutations. The motive of the study was to identify germline mutations in SMAD1 since it is a tremendous candidate for Juvenile Polyposis (JP) and long-lasting predisposition of JP leads to CRCs. No pathogenic mutations in SMAD1, SMAD2, SMAD3, or SMAD5 were found in any of the patients with JPS screened. Their result conflict with our current study and the reason may behind it is the lack of functional analysis of these genes and deep resequencing of Asian and European populations. However, there are a few limitations in our study that need to be addressed. The sample size was relatively small, thus; further larger investigations and functional studies with additional detailed environmental exposure data are defensible to validate these findings.

In conclusion, we found two SNPs (rs11100883 and rs7661662) within the SMAD1 gene that were associated with an increased risk of colorectal cancer in the Bangladeshi population. Nonetheless, such insights should inform future rational drug development by exploiting ‘pathway medicine’ approaches which in turn will decrease the mortality burden and cure costs allied with colorectal cancer.

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