Oncogenic TRIM31 confers gemcitabine resistance in pancreatic cancer via activating the NF-κB signaling pathway.
Oncogenic TRIM31 confers gemcitabine resistance in pancreatic cancer via activating the NF-κB signaling pathway.
复制标题
致癌 TRIM31 通过激活 NF-κB 信号通路赋予胰腺癌吉西他滨耐药性
作者：
Yu C;Chen S;Guo Y;Sun C
背景资料：众所周知，耐药性是癌症复发和治疗失败的主要障碍，导致胰腺癌（一种高度侵袭性肿瘤）的生存率低。确定克服耐药性的有效策略将对胰腺癌患者产生重大的临床影响。研究方法：采用Real-time PCR和Western blot检测胰腺癌细胞株和患者组织中TRIM 31蛋白和mRNA的表达。通过免疫组化分析89例人胰腺癌组织样本，以研究TRIM 31表达与胰腺癌患者临床病理特征之间的关系。功能测定，如MTT、FACS和Tunel测定，用于确定TRIM 31在人胰腺癌进展中的致癌作用。进一步采用免疫印迹法和荧光素酶法研究TRIM 31促进胰腺癌细胞耐药的机制。结果如下：TRIM 31在胰腺癌细胞系和组织中的表达显著上调，并且TRIM 31高表达与胰腺癌患者的侵袭性表型和不良预后相关。TRIM 31过表达赋予胰腺癌细胞吉西他滨抗性;然而，TRIM 31的抑制在体外和体内均使胰腺癌细胞系对吉西他滨细胞毒性敏感。此外，TRIM 31通过促进K63连接的肿瘤坏死因子受体相关因子2（TRAF 2）的多聚泛素化上调核p65水平，并维持胰腺癌细胞中核转录因子κ B（NF-κB）的活化。结论：我们的研究结果为TRIM 31是胰腺癌患者的潜在治疗靶点提供了证据。靶向TRIM 31信号可能是一种有前途的策略，以增强吉西他滨在胰腺癌化疗耐药期间的反应。
Background: Drug resistance is well known as a major obstacle for cancer recurrence and treatment failure, leading to poor survival in pancreatic cancer, which is a highly aggressive tumor. Identifying effective strategies to overcome drug resistance would have a significant clinical impact for patients with pancreatic cancer. Methods: The protein and mRNA expression of TRIM31 in pancreatic cancer cell lines and patient tissues were determined using Real-time PCR and Western blot, respectively. 89 human pancreatic cancer tissue samples were analyzed by IHC to investigate the association between TRIM31 expression and the clinicopathological characteristics of pancreatic cancer patients. Functional assays, such as MTT, FACS, and Tunel assay used to determine the oncogenic role of TRIM31 in human pancreatic cancer progression. Furthermore, western blotting and luciferase assay were used to determine the mechanism of TRIM31 promotes chemoresistance in pancreatic cancer cells. Results: The expression of TRIM31was markedly upregulated in pancreatic cancer cell lines and tissues, and high TRIM31 expression was associated with an aggressive phenotype and poor prognosis with pancreatic cancer patients. TRIM31 overexpression confers gemcitabine resistance on pancreatic cancer cells; however, inhibition of TRIM31 sensitized pancreatic cancer cell lines to gemcitabine cytotoxicity both in vitro and in vivo. Additionally, TRIM31 upregulated the levels of nuclear p65 by promoting K63-linked polyubiquitination of tumor necrosis factor receptor-associated factor 2 (TRAF2) and sustained the activation of nuclear transcription factor kappa B (NF-κB) in pancreatic cancer cells. Conclusions: Our findings provided evidence that TRIM31 is a potential therapeutic target for patients with pancreatic cancer. Targeting TRIM31 signaling may be a promising strategy to enhance gemcitabine response during pancreatic cancer chemo-resistance.
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DOI：
10.1038/labinvest.2016.109
发表时间：
2016-12
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.7
作者：
Horn, EJ;Albor, A;Kulesz-Martin, M
通讯作者：
Kulesz-Martin, M
影响因子：
3.3
作者：
Masroori N;Merindol N;Berthoux L
通讯作者：
Berthoux L
影响因子：
16
作者：
Ea, CK;Deng, L;Chen, ZJJ
通讯作者：
Chen, ZJJ
影响因子：
3.9
作者：
Lang, Valerie;Rodriguez, Manuel S.
通讯作者：
Rodriguez, Manuel S.