title: SOX9 was involved in TKIs resistance in renal cell carcinoma via Raf/MEK/ERK signaling pathway.
abstract: Renal cell carcinoma (RCC) is common genitourinary malignancy in human, 30-40% of patients with RCC would be diagnosed with metastatic RCC (mRCC). Even in the era of targeted therapy, patients with mRCC would inevitably progress due to drug resistance. Herein, exploration of the mechanisms of resistance is noteworthy to study. In the present study, we firstly reported the expression profile of SOX9 in renal carcinoma cells and tissues, and found that its expression was significantly associated with Fuhrman grading. Dual luciferase analysis confirmed that Raf/MEK/ERK pathway could directly be regulated by SOX9, and sequential experiments demonstrated that, renal carcinoma cells could sensitize to Sorafenib/Sunitinib through Raf/MEK/ERK signaling pathway inhibition regulated by SOX9 down-regulation. In a small cases with mRCC treated with Sorafenib/Sunitinib (n=38), comparative analysis showed that patients with SOX9 (-) had much better therapeutic response to TKIs than those with SOX9 (+) (PD: 9.1% vs. 56.2%, P=0.002, DCR: 90.9% vs. 43.8%, P=0.002). Based on these findings, we concluded that, SOX9 was firstly described to be highly expressed in renal cell carcinoma, and its expression was involved in TKIs drug resistance through activation of Raf/MEK/ERK pathway. In vitro, patients with SOX9 (-) was related to better response to TKIs treatment than those with SOX9 (+). SOX9 could be expected to be a promising biomarker predicting TKIs response and even expected to be another novel target in the treatment of mRCC.
authors.affiliation: Department of Pathology, West China Hospital, Sichuan University Chengdu, P. R. China.
authors.forename: Xing-Lan
authors.initials: XL
authors.lastname: Li
authors.affiliation: Department of Pathology, West China Hospital, Sichuan University Chengdu, P. R. China.
authors.forename: Xue-Qin
authors.initials: XQ
authors.lastname: Chen
authors.affiliation: Department of Pathology, West China Hospital, Sichuan University Chengdu, P. R. China.
authors.forename: Meng-Ni
authors.initials: MN
authors.lastname: Zhang
authors.affiliation: Department of Pathology, West China Hospital, Sichuan University Chengdu, P. R. China.
authors.forename: Ni
authors.initials: N
authors.lastname: Chen
authors.affiliation: Department of Pathology, West China Hospital, Sichuan University Chengdu, P. R. China.
authors.forename: Ling
authors.initials: L
authors.lastname: Nie
authors.affiliation: Department of Pathology, West China Hospital, Sichuan University Chengdu, P. R. China.
authors.forename: Miao
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Pathology, West China Hospital, Sichuan University Chengdu, P. R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Gong
authors.affiliation: Department of Urology, West China Hospital, Sichuan University Chengdu, P. R. China.
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Shen
authors.affiliation: Department of Pathology, West China Hospital, Sichuan University Chengdu, P. R. China.
authors.forename: Zheng-Zheng
authors.initials: ZZ
authors.lastname: Su
authors.affiliation: Department of Pathology, West China Hospital, Sichuan University Chengdu, P. R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Weng
authors.affiliation: Department of Pathology, West China Hospital, Sichuan University Chengdu, P. R. China.
authors.forename: Jun-Ya
authors.initials: JY
authors.lastname: Tan
authors.affiliation: Department of Urology, West China Hospital, Sichuan University Chengdu, P. R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Department of Urology, West China Hospital, Sichuan University Chengdu, P. R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zeng
authors.affiliation: Department of Pathology, West China Hospital, Sichuan University Chengdu, P. R. China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Zhou
mesh_terms: D000368:Aged; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D055758:SOX9 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D048490:raf Kinases / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D011505:Protein-Tyrosine Kinases; D048490:raf Kinases
keywords: Raf/MEK/ERK signaling pathway; Renal cell carcinoma (RCC); SOX9; resistance; tyrosine kinase inhibitors (TKIs)