三種腎血管平滑肌脂肪瘤於mTOR分子路徑之表現分析

陳昱廷、曲元正、虞凱傑、林柏宏、邵翊紘、甘弘成、黃亮鋼、莊正鏗、馮思中

林口長庚紀念醫院 外科部泌尿科

The mTOR pathway expression of three types of renal angiomyolipoma

Yu-Ting Chen, Yuan-Cheng Chu, Kai-Jie Yu, Po-Hung Lin, I-Hung Shao, Hung-Cheng Kan, Liang-Kang Huang, Cheng-Keng Chuang, See-Tong Pang

Division of Urology, Department of Surgery, LinKou Chang Gung Memorial Hospital, Taoyuan, Taiwan

Purpose:

Renal angiomyolipoma (AML) is a common benign kidney tumor consisting of dysplastic blood vessels, smooth muscle cells, and adipose tissue. There are three forms of renal AML including sporadic form, TSC-related AML, and Epithelioid AML(EAML). EAML of the kidney is a rare disease that was classified as a renal mesenchymal tumor with malignant potential by the World Health Organization in 2004. The etiology, management, and prognosis of EAML are still unclear. Everolimus belongs to one of the mTOR (mammalian target of rapamycin) inhibitors, in addition to cancer target therapy, is used to treat tuberous sclerosis complex (TSC)-related brain lesions and renal angiomyolipoma. The focus of this research is to investigate whether there are common or distinct molecular variations in three types of renal angiomyolipoma.

Materials and Methods:

Pre-operative peripheral blood was collected and used for DNA extraction. The post-operative specimens of three types of renal AML (AML, EAML and TSC-AML) were studied, including protein extraction, immunostaining, Western blot, and Sanger sequencing.

Results:

Compared to sporadic AML samples, the expression of the TSC1/2 protein, upstream of mTOR, were significantly decreased. Although the expression of the protein S6K and P70, downstream of mTOR, were significantly increased. There is no significant difference in Rheb expression among three AML types. pmTOR showed significantly higher in TSC-AML than AML and EAML. mTOR TSC-AML did not significantly differ from sporadic AML, but had a higher expression than EAML. pS6 AML had a lower expression than TSC-AML, while EAML has a slightly lower difference compared to TSC-AML. For S6, AML showed a lower expression than EAML with significant difference. The sequencing result revealed our Everolimus-treated EAML case belongs to TSC2 somatic mutation. The AMLs immunostaining data indicate that the phosphorylation in mTOR pathway were activated.

Conclusion:

AMLs tumor growth could be highly associated to TSC/mTOR pathway. mTOR inhibitor (e.g., Everolimus) can be used for treatment. Based on the immunostaining results, the TSC mutation may cause dysregulation of the downstream phosphorylation of the mTOR pathway, and the results showed that pmTOR and pS6K were slightly increased in EAML and AML. TSC mutations may not only be associated with TSC-AML, but may also affect other types of AML. Additional evidence is required to confirm this in the future.