利用tuberous sclerosis complex-1/2角色評估上皮樣腎臟血管肌肉脂肪瘤 分子病理機制
陳欽昶、林柏宏、馮思中、張英勛、劉忠一、莊正鏗* 林口長庚醫院 外科部 泌尿科
Analysis of molecular pathology features in epithelioid angiomyolipoma (eAML): involvement of the role of tuberous sclerosis complex-1/2
Po-Hung Lin, See-Tong Pang, Ying-Hsu Chang, Chin-Chang Chen, Chung-Yi Liu, Cheng-Keng Chuang *
Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taiwan.
Purpose: Epithelioid angiomyolipoma (eAML) of the kidney was considered as renal mesenchymal tumor with malignant potential. A case of metastatic eAML that was treated with Everolimus, a mTOR (mammalian target of rapamycin) inhibitor and had used in the treatment of tuberous sclerosis complex (TSC)-related renal angiomyolipoma, for us had shown decrease size of renal tumor and lung metastatic lesions. The aims of this study are to investigate the possible regulatory mechanisms of mTOR signaling pathway in malignant eAML.
Methods: The left renal tumor tissue of metastatic eAML case was obtained after operation. Next generation sequencing (NGS), polymerase chain reaction (PCR) array and Western blot were performed for evaluation of TSC gene mutation and the impact of PI3K/Akt/mTOR signaling pathway.
Results: The renal tumor section of this eAML case exhibited a frameshift deletion at TSC2 gene in chromosome 16p13.3 by NGS analysis. Further confirmation by gene-sequencing assay revealed that the tumor sample existed with a high proportion of somatic CGC to CCC mutation in the TSC-2 compared to that of its paired tissue. PCR array showed that the renal mRNA level of PI3K, AKT, TSC1, mTOR, PDK1, p70 and 4E-BP1 in tumor tissue was 2-fold larger than this of the paired tissue. In addition, our result revealed that the protein level of TSC-1 and -2 was reduced, but S6K and p70 were increased in the tumor region in comparison of the paired region.
Conclusion: Taken together, our findings suggest that the functional relationship between TSC-1/2 and mTOR had led to the use of mTOR inhibitor in eAML, might through PI3K/AKT/mTOR signaling pathway.