Potential therapeutic target secretogranin II might cooperate with hypoxia-inducible factor 1α in sunitinib-resistant renal cell carcinoma.

Autor: Fukumoto W; Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan., Yoshino H; Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan., Horike SI; Division of Functional Genomics, Advanced Science Research Center, Kanazawa University, Kanazawa, Japan., Kawakami I; Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan., Tamai M; Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan., Arima J; Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan., Kawahara I; Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan., Mitsuke A; Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan., Sakaguchi T; Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan., Inoguchi S; Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan., Meguro-Horike M; Division of Functional Genomics, Advanced Science Research Center, Kanazawa University, Kanazawa, Japan., Tatarano S; Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan., Enokida H; Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Jazyk: angličtina
Zdroj: Cancer science [Cancer Sci] 2023 Oct; Vol. 114 (10), pp. 3946-3956. Date of Electronic Publication: 2023 Aug 06.
DOI: 10.1111/cas.15914
Abstrakt: Multitargeted receptor tyrosine kinase inhibitors, including vascular endothelial growth factor (VEGF) inhibitors, such as sunitinib, have been used as the primary targeted agents for patients with recurrent or distant metastasis of advanced renal cell carcinoma (RCC). However, endogenous or acquired sunitinib resistance has become a significant therapeutic problem. Therefore, we focused on mechanisms of sunitinib resistance in RCC. First, we undertook RNA sequencing analysis using previously established sunitinib-resistant RCC (SUR-Caki1, SUR-ACHN, and SUR-A498) cells. The results showed increased expression of secretogranin II (SCG2, chromogranin C) in SUR-RCC cells compared to parental cells. The Cancer Genome Atlas database showed that SCG2 expression was increased in RCC compared to normal renal cells. In addition, the survival rate of the SCG2 high-expression group was significantly lower than that of the RCC low-expression group. Thus, we investigated the involvement of SCG2 in sunitinib-resistant RCC. In vitro analysis showed that migratory and invasive abilities were suppressed by SCG2 knockdown SUR cells. As SCG2 was previously reported to be associated with angiogenesis, we undertook a tube formation assay. The results showed that suppression of SCG2 inhibited angiogenesis. Furthermore, coimmunoprecipitation assays revealed a direct interaction between SCG2 and hypoxia-inducible factor 1α (HIF1α). Expression levels of VEGF-A and VEGF-C downstream of HIF1α were found to be decreased in SCG2 knockdown SUR cells. In conclusion, SCG2 could be associated with sunitinib resistance through VEGF regulation in RCC cells. These findings could lead to a better understanding of the VHL/HIF/VEGF pathway and the development of new therapeutic strategies for sunitinib-resistant RCC.
(© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
Databáze: MEDLINE
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