SIRT1 RNAi knockdown induces apoptosis and senescence, inhibits invasion and enhances chemosensitivity in pancreatic cancer cells
SIRT1 RNAi knockdown induces apoptosis and senescence, inhibits invasion and enhances chemosensitivity in pancreatic cancer cells
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SIRT1 RNAi 敲低诱导胰腺癌细胞凋亡和衰老、抑制侵袭并增强化疗敏感性
作者：
赵刚
依赖NAD+的脱乙酰酶sirtuin 1(SIRT1)最近被怀疑在肿瘤的发生中起作用。我们研究了SIRT1在胰腺癌中的表达，以及SIRT1靶向RNA干扰(RNAi)对胰腺癌细胞系PANC1细胞增殖和肿瘤形成的影响。对49例胰腺癌及癌旁正常胰腺组织中SIRT1的表达进行了检测。在胰腺癌组织中，SIRT1在mRNA和蛋白水平均呈高表达，且与年龄大于60岁、肿瘤直径大于4 cm、TNM较高(肿瘤范围(T)、转移至淋巴结(N)、有无远处转移(M))分期或有无淋巴结或肝转移有关。将SIRT1小发夹状RNA(ShRNA)表达载体稳定地导入PANC-1细胞，并与未转染组和PANC-1阴性RNAi细胞进行比较。PANC-1-SIRT1-RNAi细胞增殖显著降低，细胞凋亡率、G1期停滞率和衰老率明显升高。此外，FOXO3a在PANC-1-SIRT1-RNAi细胞中的表达明显上调，而对P53的表达没有显著影响。PANC-1-SIRT1-RNAi细胞体外侵袭能力明显降低，这与E-钙粘蛋白表达增加、基质金属蛋白酶表达减少有关。此外，PANC-1-SIRT1-RNAi细胞在体内的成瘤能力明显低于未转染组和PANC-1阴性RNAi细胞。这些结果提示SIRT1可能促进胰腺癌的细胞增殖和肿瘤的形成，而通过shRNA下调SIRT1可能提供一种新的治疗方法。
The NAD+-dependent deacetylase, sirtuin 1 (SIRT1), has been recently been suspected to have a role in tumorigenesis. We investigated the expression of SIRT1 in pancreatic cancer and the effect of SIRT1-targeted RNA interference (RNAi) on cell proliferation and tumor formation in a pancreatic cancer cell line, PANC1. The expression of SIRT1 was investigated in 49 specimens of pancreatic cancer and adjacent normal pancreatic tissues. SIRT1 was overexpressed in pancreatic cancer tissues at both the mRNA and protein levels, with increased SIRT1 positivity associated with tumors from patients over 60 years old, tumors larger than 4 cm, higher TNM (extent of tumor (T), the extent of spread to lymph nodes (N), and presence of distant metastasis (M)) stage or the presence of lymph node or hepatic metastases. The PANC-1 was stably transfected with a SIRT1 small hairpin RNA (shRNA) expression plasmid and compared with untransfected and PANC-1-negative RNAi cells. Proliferation of PANC-1–SIRT1–RNAi cells was significantly reduced, accompanied by increased rates of apoptosis, G1 arrest and senescence. Furthermore, FOXO3a expression was markedly upregulated in PANC-1–SIRT1–RNAi cells, but no significant difference in p53 expression was observed. The invasive ability of PANC-1–SIRT1–RNAi cells was markedly reduced in vitro, which was linked to increased E-cadherin and reduced-MMP expression. Additionally, PANC-1–SIRT1–RNAi cells had a significantly reduced capacity to form tumors in vivo compared with untransfected and PANC-1-negative RNAi cells. These results suggest that SIRT1 may promote cell proliferation and tumor formation in pancreatic cancer, and downregulation of SIRT1 using shRNA could provide a novel therapeutic treatment.
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影响因子：
37.3
作者：
Keleg, Shereen;Buchler, Peter;Ludwig, Roman;Buchler, Markus W;Friess, Helmut
通讯作者：
Friess, Helmut
影响因子：
64.8
作者：
Guarente, Leonard
通讯作者：
Guarente, Leonard
影响因子：
3.7
作者：
Ouaissi, Mehdi;Sielezneff, Igor;Ouaissi, Ali
通讯作者：
Ouaissi, Ali
DOI：
--
发表时间：
2009
期刊：
--
影响因子：
--
作者：
L. Bourguignon;W. Xia;G. Wong
通讯作者：
L. Bourguignon;W. Xia;G. Wong
影响因子：
11.2
作者：
Chu, F;Chou, PM;Rebbaa, A
通讯作者：
Rebbaa, A