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

Abstract

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.

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“…On the other hand, there is evidence that HIF-1α directly or indirectly regulates genes related to tumor proliferation, tumor cell apoptosis, metastasis, and invasion ( Rankin and Giaccia, 2016 ; Rust et al, 2019 ), and even the expression of angiogenic factors including vascular endothelial growth factor (VEGF) ( Wilson and Hay, 2011 ). VEGF is a key factor involved in tumor angiogenesis and promotes tumor progression ( Fukumoto et al, 2023 ).…”

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“…High expression of this protein upregulates the expression of VEGF and other angiogenenic factors [ 5 ]. Anti-angiogenic therapy aims to disrupt this process, thereby inhibiting tumour growth, and it has been used in a wide range of malignancies such as colorectal [ 6 ], renal [ 7 ], lung [ 8 ], hepatocellular [ 9 ], and breast cancers. The side effects of this treatment can include high blood pressure, bleeding, and wound-healing complications.…”