腎細胞癌病患的ADAMTS1–VCAN–EGFR循環導致腫瘤侵襲性與失巢凋亡抗性

 林宇璨¹, 溫玉清^1,2, 林雍偉^1,2

¹臺北市立萬芳醫院泌尿科, ²臺北醫學大學泌尿腎臟研究中心

The ADAMTS1–VCAN–EGFR axis contributes oncogenecity with invasion and anoikis resistance in renal cell carcinoma

Yu-Tsan Lin¹, Yu-Ching Wen^1,2, Yung-Wei Lin^1,2

¹Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; ²Department of Urology, School of Medicine, College of Medicine and TMU Research Center of Urology and Kidney (TMU‐RCUK), Taipei Medical University, Taipei, Taiwan

Purpose:

Metastasis, the leading cause of renal cell carcinoma (RCC) mortality, involves cancer cells resisting anoikis and invading. Until now, the role of the matrix metalloproteinase (MMP)-related enzyme, A disintegrin and metalloprotease with thrombospondin motifs 1 (ADAMTS1), in RCC anoikis regulation remains unclear.

Materials and Methods:

The clinical significance of ADAMTS1 and its associated molecules in patients with RCC was investigated

using data from the Gene Expression Omni bus (GEO) and TCGA datasets. Human phosphoreceptor tyrosine kinase (RTK) array, luciferase reporter assays, immunoprecipitation (IP) assays, western blotting, and realtime reverse-transcription quantitative polymerase chain reaction (RT–qPCR) were used to elucidate the underlying mechanisms of ADAMTS1. Functional assays, including anoikis resistance assays, invasion assays, and a Zebrafish xenotransplantation model, were conducted to assess the roles of ADAMTS1 in conferring resistance to anoikis in RCC.

Results:

This study found elevated ADAMTS1 transcripts in RCC tissues that were correlated with a poor prognosis. ADAMTS1 manipulation significantly affected cell anoikis through the mitochondrial pathway in RCC cells. Human receptor tyrosine kinase (RTK) array screening identified that epidermal growth factor receptor (EGFR) activation was responsible for ADAMTS1-induced anoikis resistance and invasion. Further investigations revealed that enzymatically active ADAMTS1-induced versican V1 (VCAN V1) proteolysis led to EGFR transactivation, which in turn, through positive feedback, regulated ADAMTS1. Additionally, ADAMTS1 can form a complex with p53 to influence EGFR signaling. In vivo, VCAN or EGFR knockdown reversed ADAMTS1-induced prometastatic characteristics of RCC. A clinical analysis revealed a positive correlation between ADAMTS1 and VCAN or the EGFR and patients with RCC with high ADAMTS1 and VCAN expression had the worst prognoses.

Conclusion:

Our results collectively uncover a novel cyclic axis involving ADAMTS1–VCAN–EGFR, which significantly contributes to RCC invasion and resistance to anoikis, serves as a promoter of tumor metastasis in RCC, thus presenting a promising therapeutic target for RCC metastasis.