When assessed by a priori defined functional pathways, tumor growth factor β (TGFβ) signaling was associated with CRC risk (<i>P</i> ≤ 0.001), with most statistically significant genes being <i>SMAD7 (P<sub>BH</sub></i> = 0.008) and <i>SMAD3 (P<sub>BH</sub></i> = 0.008), and 18 SNPs in the vitamin D receptor (VDR) binding sites (<i>P</i> = 0.036).
Additionally, miR-140 expression is decreased in the clinical primary CRC specimens and appears as a progressive reduction in the metastatic specimens, whereas Smad3 is overexpressed in the CRC samples.
Evaluation of the differential expression between carcinoma and normal mucosa showed that SMAD3rs12708491 and rs2414937, NFκB1 rs230510 and rs3821958, and RUNX3 rs6672420 were associated with several miRNAs for colorectal carcinoma.
In this phenotypic alteration, it is well known that transforming growth factor (TGF)-β/Smad3 signaling is involved; however, there is emerging new data on Smad3 phosphoisoforms: Smad3 phosphorylated at linker regions (pSmad3L), COOH-terminal regions (pSmad3C), and both (pSmad3L/C). pSmad3L/C has a pathological role in colorectal cancer.
Taken together, we demonstrated that Kindlin-1 promotes CRC progression by recruiting SARA and Smad3 to TβRI and thereby activates TGF-β/Smad3 signaling.
In this work, by deciphering the overlapping genes, crosstalking genes and pivotal regulators of both UC- and CRC-associated functional module pairs, we revealed a variety of genes (including FOS and DUSP1, etc.), transcription factors (including SMAD3 and ETS1, etc.) and miRNAs (including miR-155 and miR-196b, etc.) that may have the potential to complete the connections between UC and CRC.
Smad3(-/-) mice are deficient in the transforming growth factor beta (TGFβ) signaling molecule, SMAD3, resulting in dysregulation of the cellular pathway most commonly affected in human colorectal cancer, and develop inflammation-associated colon cancer.
Other members of the SMAD family are excellent candidates for JPS, especially SMAD2 (which, like SMAD4, is mutated somatically in colorectal cancers), SMAD3 (which causes colorectal cancer when "knocked out" in mice), SMAD5, and SMAD1.