Two sides of the story? Smad4 loss in pancreatic cancer versus head‐and‐neck cancer

Malkoski, Stephen P.; Wang, Xiaojing

doi:10.1016/j.febslet.2012.01.054

Cited by 63 publications

(63 citation statements)

References 122 publications

(196 reference statements)

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“…However, in contrast to male rats, middle-aged female rats demonstrated an increase in Smad4 mRNA expression in the reproductive organs (ovaries and uterus) relative to the pubertal and young adult groups. Given the role of Smad4 as a tumor suppressor 24 , these changes may be indicative of the Smad4 related anti-proliferative mechanisms induced in aging female rats as reproductive activity declines 25 .…”

Section: Resultsmentioning

confidence: 99%

Age-dependent expression of Pten and Smad4 genes in the urogenital system of Wistar rats

et al. 2014

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PURPOSE:To analyze Pten and Smad4 gene expression in the urogenital system of Wistar rats in differents ages. METHODS:Pten and Smad4 mRNA expression was assessed in the bladder, ventral prostate, testis, ovaries, and uterus by real-time PCR. Statistical analysis using the ANOVA (p<0.05). RESULTS:Pten levels showed a progressive age-dependent increase in the bladder (male and female) and prostate and were elevated in the ovaries of the middle-aged. In the uterus, no statistically significant differences were observed; in the testis, increased and decreased levels were seen in young adult and middle-aged rats, respectively. Smad4 expression was downregulated in the ovaries of the pubertal group but increased in the middle age group. In the uterus, Smad4 expression in the oldest group was higher than the others groups. In the testis, Smad4 expression steadily declined with age; in the prostate, it was higher in middle-aged rats than in younger rats. A similar trend was observed in the bladder of male and female middle-aged rats, compared with the pubertal group. CONCLUSION:The changes in phosphatase tensin homologue and Smad4 mRNA expression in Wistar rats appear to be associated with hormonal modifications in puberty and may be related to early follicular and testicular development.

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Section: Resultsmentioning

confidence: 99%

Age-dependent expression of Pten and Smad4 genes in the urogenital system of Wistar rats

et al. 2014

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“…TGF-β may serve as tumour suppressor, but in the advanced stage of cancer it may paradoxically hasten progression of the disease, for example by induction of epithelial-to-mesenchymal transition (EMT) [23][24][25]. The tumour suppressor gene SMAD4/DPC4/MADH4 is a core component of the TGF-β signaling pathway [17,21,23,26,27]. According to recent studies, SMAD4 plays a pivotal role in the development of metastatic PDAC [17,19,20,28].…”

Section: Introductionmentioning

confidence: 99%

Ductal adenocarcinoma of the pancreas usually retained SMAD4 and p53 protein status as well as expression of epithelial-to-mesenchymal transition markers and cell cycle regulators at the stage of liver metastasis

Liszka¹

2014

pjp

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There are limited data on the biology of metastatic pancreatic ductal adenocarcinoma (PDAC). The aim of the present study was to compare the expression of immunohistochemical markers that may be involved in the development of metastatic disease in primary PDAC and in synchronous liver metastatic tissues. Thirty-two stains (corresponding to proteins encoded by 31 genes: SMAD4, TP53, ACTA2, CDH1, CDKN1A, CLDN1, CLDN4, CLDN7, CTNNB1, EGFR, ERBB2, FN1, KRT19, MAPK1/MAPK3, MAPK14, MKI67, MMP2, MMP9, MUC1 (3 antibodies), MUC5AC, MUC6, MTOR, MYC, NES, PTGS2, RPS6, RPS6KB1, TGFB1, TGFBR1, VIM)were evaluated using tissue microarray of 26 pairs of primary PDACs and their liver metastases. There were no significant differences in expression levels of examined proteins between primary and secondary lesions. In particular, metastatic PDAC retained the primary tumour's SMAD4 protein status in all and p53 protein status in all but one case. This surprising homogeneity also involved expression levels of markers of epithelial-to-mesenchymal transition as well as cell cycle regulators studied. In conclusion, the biological profiles of primary PDACs and their liver metastases seemed to be similar. Molecular alterations of PDAC related to a set of immunohistochemical markers examined in the present study were already present at the stage of localized disease.

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confidence: 99%

“…Underscoring the tumor-suppressing role of TGF-b, mutations of TGFbRI, TGFbRII, and SMAD4 are frequently identified in gastrointestinal, pancreatic, breast, head and neck, and cervical cancers. 2,3,10 Paradoxically, SMAD3 mutations are rarely seen in tumors, despite its close structural and functional similarity to SMAD4. Moreover, interrogation of pancreatic and colon cancer genomics has found that SMAD4 mutations usually occur during late stages of tumorigenesis and are prognostic indicators of metastasis, advanced diseases, and reduced survival.…”

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Redirecting RNA splicing by SMAD3 turns TGF-β into a tumor promoter

Tripathi

Zhang

2016

Molecular & Cellular Oncology

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Transforming growth factor b (TGF-b) is a well-known growth inhibitor of normal epithelial cells, but it is also secreted by solid tumors to promote cancer progression. Our recent discovery of SMAD3-PCBP1 complex with direct RNA-binding properties has shed light on how this conversion is implemented by controlling pre-mRNA splicing patterns. Transforming growth factor b (TGF-b) is well known to be a potent growth inhibitor and tumor suppressor; however, at the time when TGF-b was discovered, it was first identified as an activity that transformed normal fibroblasts to form colonies in soft-agar in cooperation with epidermal growth factor (EGF) or TGF-a, both of which are ligands of EGF receptors (EGFR). 1 Fast forward 35 y to present time, it has been appreciated that the two seemingly opposing functions of TGF-b are cell-contextual dependent: in normal epithelial, endothelial, and hematopoietic cells. TGF-b strongly inhibits growth, but this inhibition is lost in late stages of carcinomas with elevated levels of signaling from the mitogen-activated protein kinase (MAPK) pathway sustained by oncogenic mutations. 2,3 Multiple mechanisms by which TGF-b inhibits cell growth have been unraveled, chief among them are transcriptional induction of cyclin dependent kinase (CDK) inhibitors and suppression of proto-oncogene MYC and apoptosis inducer B-cell lymphoma 2 (BCL2). On the other hand, advanced tumors are frequently found with high levels of TGF-b that promotes tumor progression by inducing epithelial to mesenchymal transition (EMT) and invasion. 4,5 Several key transcriptional targets of TGF-b including Snail Family Zinc Finger 1 (SNAl1), Zinc finger E-box binding homeobox 1 (ZEB1), high mobility group AT-Hook 2 (HMGA2), and forkhead box A1 (FOXA1) have been shown to play important roles in TGF-b-induced EMT, while other nontranscriptional mechanisms have also been reported. Despite a vast body of the literature on the nuts and bolts of how TGF-b signals, the mechanism that underpins the switch of TGF-b from a growth inhibitor to a tumor promoter still remains elusive. In searching for proteins that confer regulation of the key TGF-b pathway transcription effector SMAD3 via phosphorylation of threonine 179 (T179) in the linker region, we identified an RNA-binding protein poly(RC) binding protein 1 (PCBP1, also known as hnRNP E1), and serendipitously discovered that by partnering with PCBP1, SMAD3 is brought onto the pre-mRNA of a cancer stem cell marker gene CD44 to regulate its alternative splicing. 6 In addition to CD44, our global RNA-seq study revealed a plethora of cancers genes whose splicing patterns are altered by the SMAD3-PCBP1 interaction in favor of tumor progression. These findings let us to propose that regulation of alternative splicing by the concerted action of receptor-activated SMAD3 and PCBP1 is a key mechanism that propels TGF-b to a tumor promoter (Fig. 1).According to the current paradigm of TGF-b signaling, SMAD3 is activated by phosphorylation at the carboxyl terminus SSXS motif b...

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Two sides of the story? Smad4 loss in pancreatic cancer versus head‐and‐neck cancer

Cited by 63 publications

References 122 publications

Age-dependent expression of Pten and Smad4 genes in the urogenital system of Wistar rats

Age-dependent expression of Pten and Smad4 genes in the urogenital system of Wistar rats

Ductal adenocarcinoma of the pancreas usually retained SMAD4 and p53 protein status as well as expression of epithelial-to-mesenchymal transition markers and cell cycle regulators at the stage of liver metastasis

Redirecting RNA splicing by SMAD3 turns TGF-β into a tumor promoter

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