The significance of SMARCB1 in the pathogenesis of renal cell carcinoma with rhabdoid features

Yi-Wen Wang; Hsiang-Lin Song; Cheng-Yao Chiang; Hong-Fang Song; Hong-Yi Chang; Chien-An Chu; Yih-Lin Tuan; Kun-Hao Tsai; Yin-Chien Ou; Nan-Haw Chow; Yuh-Shyan Tsai

doi:10.1016/j.tranon.2021.101175

The significance of SMARCB1 in the pathogenesis of renal cell carcinoma with rhabdoid features

Transl Oncol. 2021 Oct;14(10):101175. doi: 10.1016/j.tranon.2021.101175. Epub 2021 Jul 6.

Authors

Affiliations

¹ Departments of Pathology, College of Medicine, National Cheng Kung University, Tainan, TAIWAN.
² Department of Pathology, National Cheng Kung University Hospital, Tainan, TAIWAN.
³ Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, TAIWAN.
⁴ Department of Biotechnology and Food Technology, College of Engineering, Southern Taiwan University of Science and Technology, Tainan, TAIWAN.
⁵ Departments of Urology, College of Medicine, National Cheng Kung University, Tainan, TAIWAN.
⁶ Departments of Pathology, College of Medicine, National Cheng Kung University, Tainan, TAIWAN; Department of Pathology, National Cheng Kung University Hospital, Tainan, TAIWAN; Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, TAIWAN. Electronic address: chownh@mail.ncku.edu.tw.
⁷ Departments of Urology, College of Medicine, National Cheng Kung University, Tainan, TAIWAN. Electronic address: youh@mail.ncku.edu.tw.

Abstract

Background: Renal cell carcinoma with rhabdoid features (RCC-RF) is an aggressive histologic variant in the adults and is usually unresponsive to standard chemotherapy.

Methods: Expression of SMARCB1/INI1 was examined in primary RCC-RF (n = 5). Stable INI1 with/without prostaglandin E2 receptor 1 (EP1) knockdown cell lines were created in the ACHN and 786-O RCC cell lines and measured for epidermal growth factor receptor (EGFR)-related signaling pathways. Chemosensitivity to targeted drugs in vitro was tested after knocking down of INI1 in both cell lines. The outcome of co-targeting of INI1 and EP1 in RCC was examined using a tumorigenicity assay.

Results: Expression of INI1 was markedly reduced at both transcriptional and translational levels in primary RCC-RF. Immunohistochemical expression of INI1 protein was lost in the nuclei of rhabdoid cells compared with conventional RCC (n = 8). Using two cell lines with different genetic background, we showed that knocking down of INI1 activates the EGFR signaling with up-regulated AKT and ERK pathways and sensitizes cancer cells to Erlotinib treatment in vitro. However, cell-line dependent effects were also demonstrated with reference to impact of INI1 or EP1 on cell growth, migration and response to Gefitinib or Everolimus treatment in vitro.

Conclusion: Inactivation of INI1 may play a role in the pathogenesis of RCC-RF. Erlotinib is recommended in the management of patients with INI1-related RCC.

Keywords: Epidermal growth factor receptor; Erlotinib; Renal cell carcinoma; Rhabdoid differentiation; SMARCB1.