Smad4 and epithelial–mesenchymal transition proteins in colorectal carcinoma: an immunohistochemical study

Abstract

Epithelial-mesenchymal transition (EMT) plays an important role in cancer metastasis. During EMT, tumor cells acquire the capacity to migrate and invade the stroma. Activation of the transforming growth factor-b (TGF-b) signaling pathway is of major importance for the initiation of EMT. Smad4, an essential protein of this pathway, is known to complex with multiple transcription factors (e.g. Snail-1, Slug, Twist-1), in various types of cancer, promoting the repression or activation of target genes. The role of Smad4 in colorectal cancer (CRC) is not straightforward so far. In the present study forty eight resected CRC tumor specimens were immunohistochemically examined in order to assess the expression of Smad4 and its association with E-cadherin, Snail-1, Slug, Twist-1 protein expression and with various pathological parameters. Smad4 was found to be positively correlated with Snail-1, Slug and Twist-1 expression (p < 0.001). On the other hand it was negatively correlated with the expression of E-cadherin (p < 0.001). Furthermore, lymphatic invasion could be clearly associated with Smad4 expression, a finding complying with the metastatic ability of EMT cells. In conclusion, Smad4 could be considered as a central component of EMT transition in human colorectal cancer that combines with transcriptional factors to reduce E-cadherin and alter the expression of the epithelial phenotype.

<p>Curcumin reverses oxaliplatin resistance in human colorectal cancer via regulation of TGF-β/Smad2/3 signaling pathway</p>

“…Smad4 plays an important role in TGF-β-induced EMT. Studies have shown that Smad4 as a central component of EMT transition in human CRC to down-regulate E-cadherin expression 39. Similar to these findings our data indicated that curcumin significantly inhibited Smad4 entry into the nucleus.…”

Upregulation of NDRG1 predicts poor outcome and facilitates disease progression by influencing the EMT process in bladder cancer

“…Moreover, TGF-β/smad signalling downregulates the expression of ZO-1, Claudin-1, and cytokeratins, followed by the degradation of tight junctions and the upregulation of N-cad expression 43,44 . In the classical pathway, SMAD4, as the common partner smad (co-SMAD), forms complexes with p-SMAD2/p-SMAD3 and then translocates into the nucleus and regulates the transcription of target genes through interactions with other DNA-binding TFs, such as snail/slug 45 . We found that SMAD4 expression significantly increased with NDRG1 overexpression but decreased with NDRG1 knockdown, primarily causing the alteration of Cytokeratin 7, Claudin-1 and N-cad expression, suggesting that NDRG1 might influence the process of EMT through modulating the expression of SMAD4 and slug in bladder cancer.…”

Dual Tumor Suppressor and Tumor Promoter Action of Sirtuins in Determining Malignant Phenotype

“…SIRT7 overexpression inhibits EMT in OSCC, where SIRT7 expression correlates inversely with patient survival. Overexpression of SIRT7 strongly decreased OSCC migration and invasion, increased E-cadherin and downregulated VIMENTIN and MMP7 protein levels by deacetylating SMAD4, a key regulator of EMT (Levy and Hill, 2005; Ioannou et al, 2018; Li et al, 2018). In contrast with other studies (Barber et al, 2012; Yu et al, 2014; Malik et al, 2015), this report provides evidence of a new role for SIRT7 in tumor metastasis.…”