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整合素连接激酶在顺铂耐药卵巢癌中的下游效应分子

Downstream Effectors of ILK in Cisplatin-Resistant Ovarian Cancer.

作者信息

Reyes-González Jeyshka M, Quiñones-Díaz Blanca I, Santana Yasmarie, Báez-Vega Perla M, Soto Daniel, Valiyeva Fatima, Marcos-Martínez María J, Fernández-de Thomas Ricardo J, Vivas-Mejía Pablo E

机构信息

Department of Biochemistry, Medical Sciences Campus, University of Puerto Rico, San Juan, PR 00936, USA.

Center for Collaborative Research in Health Disparities (CCRHD), Medical Sciences Campus, University of Puerto Rico, San Juan, PR 00936, USA.

出版信息

Cancers (Basel). 2020 Apr 4;12(4):880. doi: 10.3390/cancers12040880.

DOI:10.3390/cancers12040880
PMID:32260415
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7226328/
Abstract

Despite good responses to first-line treatment with platinum-based combination chemotherapy, most ovarian cancer patients will relapse and eventually develop platinum-resistant disease with poor prognosis. Although reports suggest that integrin-linked kinase (ILK) is a potential target for ovarian cancer treatment, identification of ILK downstream effectors has not been fully explored. The purpose of this study was to investigate the molecular and biological effects of targeting ILK in cisplatin-resistant ovarian cancer. Western blot analysis showed that phosphorylation levels of ILK were higher in cisplatin-resistant compared with cisplatin-sensitive ovarian cancer cells. Further immunohistochemical analysis of ovarian cancer patient samples showed a significant increase in phosphorylated ILK levels in the tumor tissue when compared to normal ovarian epithelium. Targeting ILK by small-interfering RNA (siRNA) treatment reduced cisplatin-resistant cell growth and invasion ability, and increased apoptosis. Differential gene expression analysis by RNA sequencing (RNA-Seq) upon ILK-siRNA transfection followed by Ingenuity Pathway Analysis (IPA) and survival analysis using the Kaplan-Meier plotter database identified multiple target genes involved in cell growth, apoptosis, invasion, and metastasis, including several non-coding RNAs. Taken together, results from this study support ILK as an attractive target for ovarian cancer and provide potential ILK downstream effectors with prognostic and therapeutic value.

摘要

尽管对铂类联合化疗一线治疗反应良好，但大多数卵巢癌患者会复发并最终发展为铂耐药疾病，预后较差。虽然有报道表明整合素连接激酶（ILK）是卵巢癌治疗的一个潜在靶点，但对ILK下游效应器的鉴定尚未得到充分探索。本研究的目的是研究靶向ILK对顺铂耐药卵巢癌的分子和生物学效应。蛋白质印迹分析表明，与顺铂敏感的卵巢癌细胞相比，顺铂耐药细胞中ILK的磷酸化水平更高。对卵巢癌患者样本进一步进行免疫组织化学分析显示，与正常卵巢上皮相比，肿瘤组织中磷酸化ILK水平显著升高。通过小干扰RNA（siRNA）处理靶向ILK可降低顺铂耐药细胞的生长和侵袭能力，并增加细胞凋亡。在转染ILK-siRNA后通过RNA测序（RNA-Seq）进行差异基因表达分析，随后进行 Ingenuity 通路分析（IPA），并使用 Kaplan-Meier 绘图仪数据库进行生存分析，确定了多个参与细胞生长、凋亡、侵袭和转移的靶基因，包括几种非编码RNA。综上所述，本研究结果支持ILK作为卵巢癌的一个有吸引力的靶点，并提供了具有预后和治疗价值的潜在ILK下游效应器。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec02/7226328/f833fb05becc/cancers-12-00880-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec02/7226328/91e036b9362c/cancers-12-00880-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec02/7226328/a1e151d5b923/cancers-12-00880-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec02/7226328/f5711747ddb5/cancers-12-00880-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec02/7226328/880bac8991e4/cancers-12-00880-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec02/7226328/78d9fa723fc7/cancers-12-00880-g005a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec02/7226328/dd269b28256e/cancers-12-00880-g006a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec02/7226328/068f5dffdcdd/cancers-12-00880-g007a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec02/7226328/f833fb05becc/cancers-12-00880-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec02/7226328/91e036b9362c/cancers-12-00880-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec02/7226328/a1e151d5b923/cancers-12-00880-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec02/7226328/f5711747ddb5/cancers-12-00880-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec02/7226328/880bac8991e4/cancers-12-00880-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec02/7226328/78d9fa723fc7/cancers-12-00880-g005a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec02/7226328/dd269b28256e/cancers-12-00880-g006a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec02/7226328/068f5dffdcdd/cancers-12-00880-g007a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec02/7226328/f833fb05becc/cancers-12-00880-g008.jpg

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