Werner syndrome as a hereditary risk factor for exocrine pancreatic cancer

Chun, Stephen G.; Yee, Nelson S.

doi:10.4161/cbt.10.5.12763

Cited by 18 publications

(10 citation statements)

References 79 publications

(83 reference statements)

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“…In this study, we examined the mRNA levels of several markers of cellular senescence including the cyclin-dependent kinase inhibitors p27 CDKN1B and p16 CDKN2A , and the DNA helicase/exonuclease-encoding gene WRN . Up-regulated expression of p27 CDKN1B and p16 CDKN2A as well as deregulation of WRN have been associated with cell cycle arrest and replicative senescence [27,28]. In TRPM7 -deficient PANC-1 cells, the mRNA levels of p16 INK4A and WRN were elevated whereas that of p27 CDKN1B remained unaltered (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, the concerted up-regulation of p16 CDKN2A and p21 CDKN1A in the TRPM7-deficient cells suggest a contributory role of TRPM7 for proliferation and survival in the pathogenesis of pancreatic neoplasia through regulation of cyclin-dependent kinase inhibitors. It is notable that targeted knockdown of TRPM7 increases the mRNA level of WRN , which is a tumor suppressive gene being mutated in patients with Werner’s syndrome that is characterized by adult-onset progeria and predisposition to various malignancies including pancreatic adenocarcinoma [28]. Ongoing studies are designed to directly determine the role of the senescence-associated genes in mediating the proliferative and pro-survival functions of TRPM7.…”

Section: Discussionmentioning

confidence: 99%

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Targeted silencing of TRPM7 ion channel induces replicative senescence and produces enhanced cytotoxicity with gemcitabine in pancreatic adenocarcinoma

et al. 2012

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The transient receptor potential TRPM7 ion channel is required for cellular proliferation in pancreatic epithelia and adenocarcinoma. To elucidate the mechanism that mediates the function of TRPM7, we examined its role in survival of pancreatic cancer cells. RNA interference-mediated silencing of TRPM7 did not induce apoptotic cell death. TRPM7-deficient cells underwent replicative senescence with up-regulation of p16CDKN2A and WRN mRNA. The combination of anti-TRPM7 siRNA and gemcitabine produced enhanced cytotoxicity as compared to gemcitabine alone. Thus, TRPM7 is required for preventing senescence, and modulation of TRPM7 expression may help improve treatment response of pancreatic cancer by combination with apoptosis-inducing agents.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Targeted silencing of TRPM7 ion channel induces replicative senescence and produces enhanced cytotoxicity with gemcitabine in pancreatic adenocarcinoma

et al. 2012

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“…Through its enzymatic functions, WRN acts on various DNA structures to facilitate DNA repair. Mutations in WRN leads to defects in DNA repair, premature aging and to cancer susceptibility [ 23 , 30 , 31 ]. Small molecules targeting DNA repair proteins have profound effects in inhibiting tumor survival.…”

Section: Discussionmentioning

confidence: 99%

Camptothecin targets WRN protein: mechanism and relevance in clinical breast cancer

Shamanna

Croteau

et al. 2016

Oncotarget

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Werner syndrome protein (WRN) is a RecQ helicase that participates in DNA repair, genome stability and cellular senescence. The five human RecQ helicases, RECQL1, Bloom, WRN, RECQL4 and RECQL5 play critical roles in DNA repair and cell survival after treatment with the anticancer drug camptothecin (CPT). CPT derivatives are widely used in cancer chemotherapy to inhibit topoisomerase I and generate DNA double-strand breaks during replication. Here we studied the effects of CPT on the stability and expression dynamics of human RecQ helicases. In the cells treated with CPT, we observed distinct effects on WRN compared to other human RecQ helicases. CPT altered the cellular localization of WRN and induced its degradation by a ubiquitin-mediated proteasome pathway. WRN knockdown cells as well as CPT treated cells became senescent and stained positive for senescence-associated β-galactosidase at a higher frequency compared to control cells. However, the senescent phenotype was attenuated by ectopic expression of WRN suggesting functional implication of WRN degradation in CPT treated cells. Approximately 5-23% of breast cancer tumors are known to respond to CPT-based chemotherapy. Interestingly, we found that the extent of CPT-induced WRN degradation correlates with increasing sensitivity of breast cancer cells to CPT. The abundance of WRN decreased in CPT-treated sensitive cells; however, WRN remained relatively stable in CPT-resistant breast cancer cells. In a large clinical cohort of breast cancer patients, we find that WRN and topoisomerase I expression correlate with an aggressive tumor phenotype and poor prognosis. Our novel observations suggest that WRN abundance along with CPT-induced degradation could be a promising strategy for personalizing CPT-based cancer chemotherapeutic regimens.

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“…Histopathologic and genetic analyses have elucidated the biological events during transformation of pancreatic epithelia into pancreatic intra-epithelial neoplasms (PanINs) and their progression to invasive adenocarcinoma. These events are associated with oncogene-induced senescence, followed by aberrant regulation of developmental pathways, tumor suppressor genes, and oncogenes, as well as epigenetic alterations ( Chun and Yee, 2010 ; Hasanali et al, 2012 ; Yee, 2011 ; Yee, 2013 ; Yee et al, 2003 ; Zhou et al, 2011 ). Further studies that focus on the mechanisms underlying these pathogenetic events will help facilitate development of biomarkers and therapy targeting the molecular phenotype of individual pancreatic tumor.…”

Section: Introductionmentioning

confidence: 99%

Aberrant over-expression of TRPM7 ion channels in pancreatic cancer: required for cancer cell invasion and implicated in tumor growth and metastasis

Yee

Kazi

et al. 2015

Biology Open

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Our previous studies in zebrafish development have led to identification of the novel roles of the transient receptor potential melastatin-subfamily member 7 (TRPM7) ion channels in human pancreatic cancer. However, the biological significance of TRPM7 channels in pancreatic neoplasms was mostly unexplored. In this study, we determined the expression levels of TRPM7 in pancreatic tissue microarrays and correlated these measurements in pancreatic adenocarcinoma with the clinicopathological features. We also investigated the role of TRPM7 channels in pancreatic cancer cell invasion using the MatrigelTM-coated transwell assay. In normal pancreas, TRPM7 is expressed at a discernable level in the ductal cells and centroacinar cells and at a relatively high level in the islet endocrine cells. In chronic pancreatitis, pre-malignant tissues, and malignant neoplasms, there is variable expression of TRPM7. In the majority of pancreatic adenocarcinoma specimens examined, TRPM7 is expressed at either moderate-level or high-level. Anti-TRPM7 immunoreactivity in pancreatic adenocarcinoma significantly correlates with the size and stages of tumors. In human pancreatic adenocarcinoma cells in which TRPM7 is highly expressed, short hairpin RNA-mediated suppression of TRPM7 impairs cell invasion. The results demonstrate that TRPM7 channels are over-expressed in a proportion of the pre-malignant lesions and malignant tumors of the pancreas, and they are necessary for invasion by pancreatic cancer cells. We propose that TRPM7 channels play important roles in development and progression of pancreatic neoplasm, and they may be explored as clinical biomarkers and targets for its prevention and treatment.

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Werner syndrome as a hereditary risk factor for exocrine pancreatic cancer

Cited by 18 publications

References 79 publications

Targeted silencing of TRPM7 ion channel induces replicative senescence and produces enhanced cytotoxicity with gemcitabine in pancreatic adenocarcinoma

Targeted silencing of TRPM7 ion channel induces replicative senescence and produces enhanced cytotoxicity with gemcitabine in pancreatic adenocarcinoma

Camptothecin targets WRN protein: mechanism and relevance in clinical breast cancer

Aberrant over-expression of TRPM7 ion channels in pancreatic cancer: required for cancer cell invasion and implicated in tumor growth and metastasis

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