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OLFM4 depletion sensitizes gallbladder cancer cells to cisplatin through the ARL6IP1/caspase-3 axis.

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机构: [1]Yan’an Hospital Affiliated to Kunming Medical University/Yan’an Hospital of Kunming City, Kunming, Yunnan 650051, China [2]Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, Yunnan 650051, China [3]Yunnan Cell Biology and Clinical Translational Research Center, Kunming, Yunnan 650051, China [4]Kunming Key Laboratory of Biotherapy, Kunming, Yunnan 650051, China [5]Department of Cancer Biotherapy Center, Yunnan Cancer Hospital/The Third Affiliated Hospital of Kunming Medical University, Kunming 650118, China [6]Department of Pathology, Guangdong Provincial People’s Hospital/Guangdong Academy of Medical Sciences, 106, Zhongshan Road II, Guangzhou 510000, China
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Gallbladder cancer (GBC) is a highly lethal malignancy that carries an extremely poor prognosis due to its chemoresistant nature. Cisplatin (CDDP) is a first-line chemotherapeutic for GBC; however, patients experienced no benefit when treated with CDDP alone. The underlying mechanisms of CDDP resistance in GBC remain largely unknown.Agilent mRNA microarray analysis was performed between paired GBC and paracarcinoma to explore differentially expressed genes that might underlie drug resistance. Gene Set Enrichment Analysis (GSEA) was employed to identify key genes mediating CDDP resistance in GBC, and immunohistochemistry was performed to validate protein expression and test correlations with clinicopathological features. In vitro and in vivo functional assays were performed to investigate the proteins' roles in CDDP resistance.Olfactomedin 4 (OLFM4) was differentially expressed between GBC and paracarcinoma and had the highest rank metric score in the GSEA. OLFM4 expression was increasingly upregulated from chronic cholecystitis to GBC in clinical tissue samples, and OLFM4 depletion decreased GBC cell proliferation and invasion. Interestingly, downregulation of OLFM4 reduced ARL6IP1 (antiapoptotic factor) expression and sensitized GBC cells to CDDP both in vitro and in vivo. The evidence indicated that CDDP could significantly increase Bax and Bad expression and activate caspase-3 cascade in OLFM4-depleted GBC cells through ARL6IP1. Clinically, lower OLFM4 expression was associated with good prognosis of GBC patients.Our results suggest that OLFM4 is an essential gene that contributes to GBC chemoresistance and could serve as a prognostic biomarker for GBC. Importantly, OLFM4 could be a potential chemotherapeutic target.Copyright © 2021. Published by Elsevier Inc.

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出版当年[2022]版:
大类 | 3 区 医学
小类 | 3 区 肿瘤学
最新[2023]版:
大类 | 2 区 医学
小类 | 3 区 肿瘤学
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Q2 ONCOLOGY
最新[2023]版:
Q1 ONCOLOGY

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第一作者机构: [1]Yan’an Hospital Affiliated to Kunming Medical University/Yan’an Hospital of Kunming City, Kunming, Yunnan 650051, China [2]Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, Yunnan 650051, China [3]Yunnan Cell Biology and Clinical Translational Research Center, Kunming, Yunnan 650051, China [4]Kunming Key Laboratory of Biotherapy, Kunming, Yunnan 650051, China
通讯作者:
通讯机构: [1]Yan’an Hospital Affiliated to Kunming Medical University/Yan’an Hospital of Kunming City, Kunming, Yunnan 650051, China [2]Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, Yunnan 650051, China [3]Yunnan Cell Biology and Clinical Translational Research Center, Kunming, Yunnan 650051, China [4]Kunming Key Laboratory of Biotherapy, Kunming, Yunnan 650051, China [*1]Yan’an Hospital Affiliated to Kunming Medical University/Yan’an Hospital of Kunming City, Kunming, Yunnan 650051, China.
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