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Cathepsin D Expression and Gemcitabine Resistance in Pancreatic Cancer.

ABSTRACT: Background:Cathepsin-D (CatD), owing to its dual role as a proteolytic enzyme and as a ligand, has been implicated in cancer progression. The role of CatD in pancreatic ductal adenocarcinoma is unknown. Methods:CatD expression quantified by immunohistochemistry of tumor-tissue microarrays of 403 resected pancreatic cancer patients from the ESPAC-Tplus trial, a translational study within the ESPAC (European Study Group for Pancreatic Cancer) trials, was dichotomously distributed to low and high H scores (cut off 22.35) for survival and multivariable analysis. The validation cohort (n?=?69) was recruited based on the hazard ratio of CatD from ESPAC-Tplus. 5-fluorouracil-, and gemcitabine-resistant pancreatic cancer cell lines were employed for mechanistic experiments. All statistical tests were two-sided. Results:Median overall survival was 23.75?months and median overall survival for patients with high CatD expression was 21.09 (95% confidence interval [CI] = 17.31 to 24.80) months vs 27.20?(95% CI = 23.75 to 31.90) months for low CatD expression (?2 LR, 1DF = 4.00; P?=?.04). Multivariable analysis revealed CatD expression as a predictive marker in gemcitabine-treated (z stat = 2.33; P?=?.02) but not in 5-fluorouracil-treated (z stat = 0.21; P?=?.82) patients. An independent validation cohort confirmed CatD as a negative predictive marker for survival (?2 LR, 1DF = 6.80; P?=?.009) and as an independent predictive marker in gemcitabine-treated patients with a hazard ratio of 3.38 (95% CI = 1.36 to 8.38, P =?.008). Overexpression of CatD was associated with a concomitant suppression of the acid sphingomyelinase, and silencing of CatD resulted in upregulation of acid sphingomyelinase with rescue of gemcitabine resistance. Conclusions:Adjuvant gemcitabine is less effective in pancreatic ductal adenocarcinoma with high CatD expression, and thus CatD could serve as a marker for biomarker-driven therapy.

SUBMITTER: Mahajan UM

PROVIDER: S-EPMC7050148 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Cathepsin D Expression and Gemcitabine Resistance in Pancreatic Cancer.

Mahajan Ujjwal M UM Goni Elisabetta E Langhoff Enno E Li Qi Q Costello Eithne E Greenhalf William W Kruger Stephan S Ormanns Steffen S Halloran Christopher C Ganeh Paula P Marron Manuela M Lämmerhirt Felix F Zhao Yue Y Beyer Georg G Weiss Frank-Ulrich FU Sendler Matthias M Bruns Christiane J CJ Kohlmann Thomas T Kirchner Thomas T Werner Jens J D'Haese Jan G JG von Bergwelt-Baildon Michael M Heinemann Volker V Neoptolemos John P JP Büchler Markus W MW Belka Claus C Boeck Stefan S Lerch Markus M MM Mayerle Julia J

JNCI cancer spectrum 20190816 1

<h4>Background</h4>Cathepsin-D (CatD), owing to its dual role as a proteolytic enzyme and as a ligand, has been implicated in cancer progression. The role of CatD in pancreatic ductal adenocarcinoma is unknown.<h4>Methods</h4>CatD expression quantified by immunohistochemistry of tumor-tissue microarrays of 403 resected pancreatic cancer patients from the ESPAC-Tplus trial, a translational study within the ESPAC (European Study Group for Pancreatic Cancer) trials, was dichotomously distributed to ...[more]

PMID: 32296755

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Project description:Background Pancreatic ductal adenocarcinoma (PDAC) has the worst five-year overall survival rate among all cancer types. Acquired chemoresistance is considered one of the main reasons for this dismal prognosis, and the mechanism of chemoresistance is unknown. Methods We previously identified a subpopulation of chemoresistant CD44high-expressing PDAC cells. Subsequently, we selected the candidate gene, gamma-aminobutyric acid receptor subunit Pi (GABRP), from three Gene Expression Omnibus datasets as the potential CD44 downstream target mediating the gemcitabine resistance. Loss and gain of function such as stable knockdown of CD44 by small hairpin (sh) RNA-mediated silencing technique and overexpression (O/E) of CD44s had been studied for comparing the gemcitabine resistance among CD44high-expressing cells, shCD44 cells, CD44low-expressing cells and O/E CD44s expressing cells. Functional assays including cell viability, colony formation, invasion, quantitative PCR and western blotting techniques were performed to validate the roles of CD44 and GABRP playing in mediating the gemcitabine resistance in pancreatic cancer cells. Results CD44s depletion significantly reduced gemcitabine resistance in shCD44 single clone cells compared to CD44high-expressing cells. Knockdown of CD44 cells formed less colonies, became less invasive and remarkably decreased the mRNA level of GABRP. While overexpression of CD44s had the opposite effect on gemcitabine resistance, colony formation and invasive property. Of note, long term gemcitabine resistant pancreatic cancer cells detected increased expression of CD44 and GABRP. Clinically, GABRP expression was significantly upregulated in the tissues of patients with pancreatic cancer compared to the normal samples, and the overall survival rate of patients with low GABRP expression was longer. CD44 and GABRP co-expression was positively correlated in 178 pancreatic cancer patients. Conclusion Our findings suggest that GABRP may serve as a CD44s downstream target to diminish gemcitabine resistance in pancreatic cancer, and both CD44s and GABRP molecules have the potential to become prognostic biomarkers for PDAC patients with gemcitabine resistance.

Project description:BackgroundTM4SF1 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and affects the development of this cancer. Also, multidrug resistance (MDR) is generally associated with tumor chemoresistance in pancreatic cancer. However, the correlation between TM4SF1 and MDR remains unknown. This research aims to investigate the effect of TM4SF1 on gemcitabine resistance in PDAC and explore the possible molecular mechanism between TM4SF1 and MDR.MethodsThe expression of TM4SF1 was evaluated in pancreatic cancer cell lines and human pancreatic duct epithelial (HPDE) cell lines by quantitative RT-PCR. TM4SF1 siRNA transfection was carried out using Hiperfect transfection reagent to knock down TM4SF1. The transcripts were analyzed by quantitative RT-PCR, RT-PCR and western blotting for further study. The cell proliferation and apoptosis were obtained to investigate the sensitivity to gemcitabine of pancreatic cancer cells after silencing TM4SF1 in vitro. We demonstrated that cell signaling of TM4SF1 mediated chemoresistance in cancer cells by assessing the expression of multidrug resistance (MDR) genes using quantitative RT-PCR. In vivo, we used orthotopic pancreatic tumor models to investigate the effect of proliferation after silencing TM4SF1 by a lentivirus-mediated shRNA in MIA PaCa-2 cell lines.ResultsThe mRNA expression of TM4SF1 was higher in seven pancreatic cancer cell lines than in HPDE cell lines. In three gemcitabine-sensitive cell lines (L3.6pl, BxPC-3, SU86.86), the expression of TM4SF1 was lower than that in four gemcitabine-resistant cell lines (MIA PaCa-2, PANC-1, Hs766T, AsPC-1). We evaluated that TM4SF1 was a putative target for gemcitabine resistance in pancreatic cancer cells. Using AsPC-1, MIA PaCa-2 and PANC-1, we investigated that TM4SF1 silencing affected cell proliferation and increased the percentages of cell apoptosis mediated by treatment with gemcitabine compared with cells which were treated with negative control. This resistance was associated with the expression of multidrug resistance genes including ABCB1 and ABCC1. In vivo, silencing of TM4SF1 in MIA PaCa-2 cell lines increased the effectiveness of gemcitabine-based treatment in orthotopic pancreatic tumor models evaluated using noninvasive bioluminescent imaging.ConclusionThese findings suggest that TM4SF1 is a surface membrane antigen that is highly expressed in pancreatic cancer cells and increases the chemoresistance to gemcitabine. Thus, TM4SF1 may be a promising target to overcome the chemoresistance of pancreatic cancer.

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Cathepsin D Expression and Gemcitabine Resistance in Pancreatic Cancer.

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Cathepsin D Expression and Gemcitabine Resistance in Pancreatic Cancer.

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