Myoferlin silencing inhibits VEGFR2-mediated proliferation of metastatic clear cell renal cell carcinoma

• Published in: Scientific reports Vol. 9; no. 1; pp. 12656 - 8
• Main Authors: An, Hyo Jung, Song, Dae Hyun, Koh, Hyun Min, Kim, Yu-Min, Ko, Gyung Hyuck, Lee, Jeong-Hee, Lee, Jong Sil, Yang, Jung Wook, Kim, Min Hye, Seo, Deok Ha, Jang, Se Min, Kim, Dong Chul
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.09.2019; Nature Publishing Group
• Subjects: 13/1; 13/105; 13/109; 13/51; 38/77; 692/4025; 692/4028; 692/53; Adult; Aged; Aged, 80 and over; Breast; Breast cancer; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - pathology; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; Clear cell-type renal cell carcinoma; Endocytosis; Endothelial Cells - metabolism; Female; Gene Expression Regulation, Neoplastic; Gene Silencing; Humanities and Social Sciences; Humans; Invasiveness; Kidney cancer; Kidney Neoplasms - genetics; Kidney Neoplasms - pathology; Male; Melanoma; Membrane fusion; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metastases; Metastasis; Middle Aged; mRNA; multidisciplinary; Multivariate Analysis; Muscle Proteins - genetics; Muscle Proteins - metabolism; Neoplasm Metastasis; Nephrectomy; Pancreas; Patients; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism; Proportional Hazards Models; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Signal Transduction - genetics; Statistical analysis; Survival Analysis; Tumor cell lines; Vascular endothelial growth factor; Vascular Endothelial Growth Factor Receptor-2 - genetics; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Vascular endothelial growth factor receptors; Wound Healing
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-48968-7

Recently, ramucirumab, a drug that targets vascular endothelial growth factor receptor (VEGFR), was clinically approved; therefore, we evaluated VEGFR2 expression and its predictive roles in tumor progression in clear cell renal cell carcinoma (CCRCC). Since we do not have many options for treating aggressive renal cell carcinoma patients, the application of anti-VEGFR2 therapy might be useful. Myoferlin (MYOF) is a 230 kDa transmembrane multi-C2-domain protein that contributes to plasma membrane repair, fusion, and endocytosis and is overexpressed in several invasive cancer cell lines, including breast, pancreas, and malignant melanoma. It forms a complex with VEGFR2 to inhibit VEGFR2 degradation. In this study, a total of 152 patients who had undergone nephrectomy for CCRCC were enrolled. Based on tissue microarray (TMA) blocks, the positive intensity and high proportion of MYOF showed a statistically significant correlation with the negative intensity (p < 0.001) and low proportion (p < 0.001) of VEGFR2, respectively. In addition, Fuhrman’s nuclear grade ≥3 showed a significant correlation with VEGFR2 expression. In multivariate analysis, CCRCC patients with positive MYOF and negative VEGFR2 expression demonstrated poor clinical outcomes. We confirmed that positive MYOF expression and negative VEGFR2 expression were positively correlated in this CCRCC population. Knocking down MYOF in Caki-1 cells resulted in the downregulation of VEGFR2 at both mRNA and protein levels. Wound healing assays revealed that the loss of MYOF in Caki-1 cells decreased cell confluence compared to that in control cells. We demonstrated that MYOF influences cellular proliferation of the metastatic CCRCC cell line by regulating VEGFR2 degradation. Combined therapies targeting the MYOF and VEGFR2 pathways might be effective against metastatic CCRCC to increase patient survival.