Loss of the Smad3 expression increases susceptibility to tumorigenicity in human gastric cancer

Han, Sang Uk; Kim, Heung Tae; Seong, Do Hwan; Kim, Yong Suk; Park, Yoon Soo; Bang, Yung Jue; Yang, Han‐Kwang; Kim, Seong‐Jin

doi:10.1038/sj.onc.1207259

Cited by 120 publications

(106 citation statements)

References 58 publications

(53 reference statements)

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“…expressing Smad3 and SNU638 cells expressing wildtype TbRII exhibited restoration of TGF-b signaling and reduced tumorigenicity (Chang et al, 1997;Han et al, 2004). These cells showed positive expression of CEAs.…”

Section: Discussionmentioning

confidence: 99%

“…Transfection of Smad3 into SNU484 cells enhanced both basal and TGF-b-dependent activities of the TGF-b-dependent reporters, p3TP-Lux and SBE-Luc, and reduces tumorigenesis (Han et al, 2004). Western analysis revealed that high levels of Smad3 protein were detected in SNU484 cells expressing wild-type Smad3 ( Figure 5a).…”

Section: Expression Of Wild-type Tbrii Restores Tgf-b Signaling and Imentioning

confidence: 97%

“…Introduction of Smad3 restores TGF-b signaling and induces the expression of CEA in SNU484 cells SNU484 cells express low to undetectable levels of Smad3 protein (Han et al, 2004). Transfection of Smad3 into SNU484 cells enhanced both basal and TGF-b-dependent activities of the TGF-b-dependent reporters, p3TP-Lux and SBE-Luc, and reduces tumorigenesis (Han et al, 2004).…”

Section: Expression Of Wild-type Tbrii Restores Tgf-b Signaling and Imentioning

confidence: 99%

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CEACAM5 and CEACAM6 are major target genes for Smad3-mediated TGF-β signaling

et al. 2007

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The carcinoembryonic antigen (CEAs) family consists of a large group of evolutionarily and structurally divergent glycoproteins. The transforming growth factor-b (TGF-b) signaling pathway has been implicated in the stimulation of CEA secretion in TGF-b-sensitive colon cells, thereby possibly modulating cell adhesion and differentiation. However, the specific CEAs targeted by TGF-b signaling or underlying mechanism of the expression of CEAs has not yet been clarified. In this study, we investigated the specific CEAs targeted by the TGF-b signaling pathway. In nine human gastric cancer cell lines examined, TGF-bresponsive cell lines showed positive expression of CEAs. Expression patterns of CEA proteins correlated well with the level of CEA (CEACAM5) and CEACAM6 transcripts in these cell lines, but CEACAM1 expression was not observed in all of these cells. To investigate the role of TGF-b signaling in CEA expression, we selected two TGFb unresponsive gastric cancer cell lines; SNU638 cells that contain a mutation in the TGF-b type II receptor and SNU484 cells that express low to undetectable level of the TGF-b pathway intermediate protein, Smad3. Restoration of TGF-b signaling in these cells induced expression of the CEAs and increased activity of both CEA (CEACAM5) and CEACAM6 promoters. CEA expression was observed in the epithelium of the stomach of wild-type mice, but was markedly decreased in Smad3 null mice. These findings suggest that CEA (CEACAM5) and CEACAM6 are major target genes for Smad3-mediated TGF-b signaling.

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Section: Discussionmentioning

confidence: 99%

Section: Expression Of Wild-type Tbrii Restores Tgf-b Signaling and Imentioning

confidence: 97%

Section: Expression Of Wild-type Tbrii Restores Tgf-b Signaling and Imentioning

confidence: 99%

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CEACAM5 and CEACAM6 are major target genes for Smad3-mediated TGF-β signaling

et al. 2007

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“…Smad2 has also been found to be mutated at very low frequency in colorectal and lung cancers (Takagi et al, 1998;Yanagisawa et al, 2000). In case of Smad3, 37.5% of human gastric cancer tissues showed no or low expression of Smad3 (Han et al, 2004). Recovery of Smad3 signaling blocked tumorigenicity in mice, indicating that Smad3 has a role in tumor suppression in the early stages of gastric tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

“…Previously, Han et al (2004) showed that the introduction of Smad3 into a human gastric cancer cell line that does not express Smad3 restores TGF-b responsiveness and E-cadherin expression. In the present study, we aimed to profile and characterize miRNAs from the same human gastric cancer cell lines (SNU484-LPCX and SNU484-Smad3) to identify potential miRNA links between Smad3 and E-cadherin.…”

Section: Introductionmentioning

confidence: 99%

Smad3 regulates E-cadherin via miRNA-200 pathway

Ahn

Young

et al. 2011

Oncogene

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To identify potential microRNA (miRNA) links between Smad3, a mediator of TGF-b (transforming growth factor-b) signaling, and E-cadherin, we characterized the miRNA profiles of two gastric cancer cell lines: SNU484-LPCX, which does not express Smad3, and SNU484-Smad3, in which Smad3 is overexpressed. We found that among differentially expressed miRNAs, miR-200 family members are overexpressed in SNU484-Smad3 cells. Subsequent studies, including analysis of the effects of silencing Smad3 in SNU484-Smad3 cells and a luciferase reporter assay, revealed that Smad3 directly binds to a Smad-binding element located in the promoter region of miR-200b/a, where it functions as a transcriptional activator. TGF-b did not affect the regulatory role of Smad3 in transcription of miR-200 and expression of epithelial-mesenchymal transition markers. We conclude that Smad3 regulates, at the transcriptional level, miR-200 family members, which themselves regulate ZEB1 and ZEB2, known transcriptional repressors of E-cadherin, at the posttranscriptional level in a TGF-b-independent manner. This represents a novel link between Smad3 and posttranscriptional regulation by miRNAs in epithelial-mesenchymal transition in gastric cancer cells.

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Dual inhibition of DNMTs and EZH2 can overcome both intrinsic and acquired resistance of myeloma cells to IMiDs in a cereblon‐independent manner

et al. 2017

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Thalidomide and its derivatives, lenalidomide and pomalidomide (also known as IMiDs), have significantly changed the treatment landscape of multiple myeloma, and the recent discovery of cereblon (CRBN) as their direct biological target has led to a deeper understanding of their complex mechanism of action. In an effort to comprehend the precise mechanisms behind the development of IMiD resistance and examine whether it is potentially reversible, we established lenalidomide‐resistant (‐LR) and pomalidomide‐resistant (‐PR) human myeloma cell lines from two IMiD‐sensitive cell lines, OPM2 and NCI‐H929, by continuous culture in the presence of lenalidomide or pomalidomide for 4–6 months, until acquirement of stable resistance. By assessing genome‐wide DNA methylation and chromatin accessibility in these cell lines, we found that acquired IMiD resistance is associated with an increase in genome‐wide DNA methylation and an even greater reduction in chromatin accessibility. Transcriptome analysis confirmed that resistant cell lines are mainly characterized by a reduction in gene expression, identifying SMAD3 as a commonly downregulated gene in IMiD‐resistant cell lines. Moreover, we show that these changes are potentially reversible, as combination of 5‐azacytidine and EPZ‐6438 not only restored the observed accessibility changes and the expression of SMAD3, but also resensitized the resistant cells to both lenalidomide and pomalidomide. Interestingly, the resensitization process was independent of CRBN. Our data suggest that simultaneous inhibition of DNA methyl transferases and EZH2 leads to an extensive epigenetic reprogramming which allows myeloma cells to (re)gain sensitivity to IMiDs.

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Loss of the Smad3 expression increases susceptibility to tumorigenicity in human gastric cancer

Cited by 120 publications

References 58 publications

CEACAM5 and CEACAM6 are major target genes for Smad3-mediated TGF-β signaling

CEACAM5 and CEACAM6 are major target genes for Smad3-mediated TGF-β signaling

Smad3 regulates E-cadherin via miRNA-200 pathway

Dual inhibition of DNMTs and EZH2 can overcome both intrinsic and acquired resistance of myeloma cells to IMiDs in a cereblon‐independent manner

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