Down regulation of CAII is associated with tumor differentiation and poor prognosis in patients with pancreatic cancer

Sheng, Weiwei; Dong, Ming; Zhou, Jianping; Li, Xin; Dong, Qi

doi:10.1002/jso.23282

Cited by 15 publications

(15 citation statements)

References 32 publications

(49 reference statements)

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“…In general, one of the most important roles of retinoids is a fine regulation of differentiation both in normal and pathological states [22]. It has been recently shown that a down-regulation of the differentiation marker CA2 is associated with a poor prognosis of patients with PDAC [26]. Our data also point out the importance of CA2 for the prediction of OS of PDAC patients.…”

Section: Link Between Retinoids As Well As Their Receptors and Emt Csupporting

confidence: 70%

Reduced retinoids and retinoid receptors' expression in pancreatic cancer: A link to patient survival

et al. 2014

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Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers in the world. All-trans retinoic acid (ATRA) is the major physiologically active form of vitamin A, regulating expression of many genes. Disturbances of vitamin A metabolism are prevalent in some cancer cells. The main aim of this work was to investigate deeply the components of retinoid signaling in PDAC compared to in the normal pancreas and to prove the clinical importance of retinoid receptor expression. For the study, human tumor tissues obtained from PDAC patients and murine tumors from the orthotopic Panc02 model were used for the analysis of retinoids, using high performance liquid chromatography mass spectrometry and real-time RT-PCR gene expression analysis. Survival probabilities in univariate analysis were estimated using the Kaplan-Meier method and the Cox proportional hazards model was used for the multivariate analysis. In this work, we showed for the first time that the ATRA and all-trans retinol concentration is reduced in PDAC tissue compared to their normal counterparts. The expression of RARα and β as well as RXRα and β are down-regulated in PDAC tissue. This reduced expression of retinoid receptors correlates with the expression of some markers of differentiation and epithelial-to-mesenchymal transition as well as of cancer stem cell markers. Importantly, the expression of RARα and RXRβ is associated with better overall survival of PDAC patients. Thus, reduction of retinoids and their receptors is an important feature of PDAC and is associated with worse patient survival outcomes.

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Section: Link Between Retinoids As Well As Their Receptors and Emt Csupporting

confidence: 70%

Reduced retinoids and retinoid receptors' expression in pancreatic cancer: A link to patient survival

et al. 2014

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“…Furthermore, earlier observations of the acid response of store-operated calcium entry (64) and mTORC1 (65) were made in the absence of CO 2 /HCO 3 Ϫ , arguing for H ϩ ions as the key regulators. Growing evidence points to a negative correlation between the expression of CA i isoforms, such as CAII, and cancer disease severity (11,(13)(14)(15). Importantly for disease progression, CAII down-regulation would help to protect cytoplasmic pH from pCO 2 fluctuations and bestow cancer cell pH with a greater degree of autonomy from extracellular influences, such as those arising from intermittent blood flow (73).…”

Section: Discussionmentioning

confidence: 99%

Intracellular Carbonic Anhydrase Activity Sensitizes Cancer Cell pH Signaling to Dynamic Changes in CO2 Partial Pressure

Hulı́ková

Aveyard

Harris

et al. 2014

Journal of Biological Chemistry

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“…The dismal prognosis of pancreatic cancer has been linked to poor tumor differentiation (2, 3), a widely accepted index for prediction of therapeutic response and prognosis of many cancers including pancreatic cancer. Despite significant clinical implications, however, the molecules and signaling pathways that regulate the differentiation of pancreatic cancer remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

DNA-Methyltransferase 1 Induces Dedifferentiation of Pancreatic Cancer Cells through Silencing of Krüppel-Like Factor 4 Expression

Xie

Yan

et al. 2017

Clinical Cancer Research

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Objective The dismal prognosis of pancreatic cancer has been linked to poor tumor differentiation. However, molecular basis of pancreatic cancer differentiation and potential therapeutic value of the underlying molecules remain unknown. We investigated the mechanistic underexpression of Krüppel-like factor 4 (KLF4) in pancreatic cancer and defined a novel epigenetic pathway of its activation for pancreatic cancer differentiation and treatment. Design Expressions of KLF4 and DNMT1 in pancreatic cancer tissues were determined by immunohistochemistry and the genetic and epigenetic alterations of KLF4 in and KLF4’s impact on differentiation of pancreatic cancer were examined using molecular biology techniques. The function of dietary 3,3’-diindolylmethane (DIM) on miR-152/DNMT1/KLF4 signaling in pancreatic cancer was evaluated using both cell culture and animal model. Results Overexpression of DNMT1 and promoter hypermethylation contributed to decreased KLF4 expression in and associated with poor differentiation of pancreatic cancer. Manipulation of KLF4 expression significantly affected differentiation marker expressions in pancreatic cancer cells. DIM treatment significantly induced miR-152 expression, which blocked DNMT1 protein expression and its binding to KLF4 promoter region, and consequently, reduced promoter DNA methylation and activated KLF4 expression in pancreatic cancer cells. Additionally, DIM treatment caused significant inhibition of cell growth in vitro and tumorigenesis in animal model of pancreatic cancer. Conclusions This is the first demonstration that dysregulated KLF4 expression associates with poor differentiation of pancreatic cancer. Epigenetic activation of miR-152/DNMT1/KLF4 signaling pathway by dietary DIM causes differentiation and significant growth inhibition of pancreatic cancer cells, highlighting its translational implications for pancreatic and other cancers.

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Down regulation of CAII is associated with tumor differentiation and poor prognosis in patients with pancreatic cancer

Abstract: This study suggests the clinical significance of CAI, CAII and p53 expression in pancreatic cancer and provides evidence for AZ as a potential target for controlling pancreatic cancer.

Cited by 15 publications

References 32 publications

Reduced retinoids and retinoid receptors' expression in pancreatic cancer: A link to patient survival

Reduced retinoids and retinoid receptors' expression in pancreatic cancer: A link to patient survival

Intracellular Carbonic Anhydrase Activity Sensitizes Cancer Cell pH Signaling to Dynamic Changes in CO2 Partial Pressure

DNA-Methyltransferase 1 Induces Dedifferentiation of Pancreatic Cancer Cells through Silencing of Krüppel-Like Factor 4 Expression

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