菸鹼胺-氮-甲基轉移酶藉由誘導第二型基質金屬蛋白酶表現促進透明細胞型腎細胞癌之侵犯能力

楊琮誠

doi:10.6342/NTU.2008.02837

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菸鹼胺-氮-甲基轉移酶藉由誘導第二型基質金屬蛋白酶表現促進透明細胞型腎細胞癌之侵犯能力

Nicotinamide-N-methyltransferase Enhances Invasive Ability of Clear Cell Renal Cell Carcinoma by Inducing Matrix Metalloprotease-2 Expression

楊琮誠 , Masters　　Advisor：林榮耀　　

英文 DOI： 10.6342/NTU.2008.02837

腎細胞癌；菸鹼胺-氮-甲基轉移； Renal cell carcinoma ； Nicotinamide N-methyltransferase ； Matrix metalloprotease-2 ； PI3K ； Akt

Abstract │ Reference (46) │ Altmetrics

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Renal cell carcinoma (RCC) accounts for 2 ~ 3% of all adult malignancies, and clear cell renal cell carcinoma (ccRCC) is the major and aggressive subtype of RCC. Because RCC responds poorly to traditional therapies such as chemotherapy and radiotherapy, surgery remains to be the main remedy. Therefore, it is important to identify RCC-associated genes involved in tumorigenesis and finally develop new approaches to diagnosis and therapy. In our previous studies, we have identified 201 up-regulated and 182 down-regulated genes in ccRCC by analyzing full-length enriched cDNA libraries of ccRCC and normal kidney. Nicotinamide N-methyltransferase (NNMT), one of the most up-regulated genes, was found to be overexpressed in ccRCC. Besides, recent studies have demonstrated that NNMT overexpression was also found in thyroid and colorectal tumors. Hence, the specific aim of our research is to investigate the roles of NNMT overexpression in ccRCC.
In this study, we used human embryonic kidney cells (HEK293) without endogenous NNMT expression for the following experiments. By using quantitative real-time PCR analysis, we observed that mRNA expression of matrix metalloprotease-2 (MMP-2) was up-regulated in the HEK293/NNMT cells. The results of western blot and gelatin zymography also showed that HEK293/NNMT cells had higher MMP-2 secretion. To further investigate the phenotype caused by MMP-2 up-regulation, we performed in vitro cell invasion assays to study the invasive activities with the HEK293/NNMT and HEK293/VEC cells, and the results revealed that NNMT overexpression promoted the HEK293 cell invasiveness. Besides, the invasive ability was suppressed by either MMP-2 inhibitor or MMP-2 siRNA.
To delineate signaling pathway involved in MMP-2 up-regulation induced by NNMT, we used specific inhibitors to impede many signaling pathways and observed that either PI3K inhibitor (LY294002) or Akt inhibitor IV inhibited MMP-2 expression and MMP-2 promoter activity, and suppressed cell invasive ability. In addition, knockdown of Akt or NNMT by specific siRNAs inhibited MMP-2 expression and suppressed cell invasive ability. Taken together, our data suggest that NNMT overexpression might contribute to invasive phenotype in ccRCC by inducing MMP-2 expression via PI3K/Akt signaling pathway.

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