title: Adenovirus-mediated LRIG1 expression enhances the chemosensitivity of bladder cancer cells to cisplatin.
abstract: Cisplatin (cis-diaminodichloroplatinum, CDDP) is one of the most effective chemotherapeutic agents that has been widely used in the treatment of many malignancies, including muscle invasive bladder cancer. However, development of CDDP resistance in cancer cells is a major obstacle to the effective treatment of bladder cancer. Therefore, the development of chemosensitizers to overcome the acquired resistance to chemotherapeutic agents is crucial. Previous studies have confirmed that the epidermal growth factor receptor (EGFR) and its signaling pathways are important in the chemoresistance of cancer cells against CDDP‑induced cell apoptosis. In a preliminary study we showed that leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is the natural ligand of EGFR, and that the extracellular leucine-rich repeat (LRR) domain and immunoglobulin-like domains of LRIG1 were able to bind to the extracellular domain of EGFR, resulting in the downregulation of EGFR expression. Based on these findings, we hypothesized that LRIG1 may enhance the chemosensitivity of bladder cancer cells to CDDP. In the present study, LRIG1 was overexpressed by the adenovirus vector to determine the effect of LRIG1 on chemosensitivity in the T24 bladder cancer cell line and explored the possible mechanisms. The results showed that CDDP inhibited the growth of the T24 cell line and induced activation of EGFR. Overexpression of LRIG1 increased the inhibitory effect of CDDP on the T24 cell line, which may be associated with inactivation of the EGFR signaling pathway, followed by the decrease of Bcl-2 expression and a concomitantly induced expression of Bax. Based on these results, we concluded that the upregulation of LRIG1 expression inhibited the EGFR signaling pathway, activated the mitochondrial pathway of apoptosis and eventually increased the sensitivity of bladder cancer cells to CDDP.
authors.affiliation: Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, P.R. China.
authors.forename: Zejun
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Department of Urology, Ningbo First Hospital, Medical College of Ningbo University, Ningbo, Zhejiang 315010, P.R. China.
authors.forename: Junhui
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
authors.forename: Fan
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
authors.forename: Weiming
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Urology, Ningbo First Hospital, Medical College of Ningbo University, Ningbo, Zhejiang 315010, P.R. China.
authors.forename: Guohai
authors.initials: G
authors.lastname: Xie
authors.affiliation: Department of Urology, Ningbo First Hospital, Medical College of Ningbo University, Ningbo, Zhejiang 315010, P.R. China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, P.R. China.
authors.forename: Shujie
authors.initials: S
authors.lastname: Xia
authors.affiliation: Department of Urology, Ningbo First Hospital, Medical College of Ningbo University, Ningbo, Zhejiang 315010, P.R. China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Cheng
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D005822:Genetic Vectors; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D015398:Signal Transduction; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; C484445:LRIG1 protein, human; D008562:Membrane Glycoproteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D002945:Cisplatin