Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical, University, Guiyang, Guizhou 550004, China.
Theranostics. 2018 May 11;8(12):3224-3236. doi: 10.7150/thno.23259. eCollection 2018.
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. 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. 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 and . 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. 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.
耐药性是癌症复发和治疗失败的主要障碍，这导致胰腺癌患者的生存预后较差，而胰腺癌是一种侵袭性很强的肿瘤。因此，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。采用实时 PCR 和 Western blot 分别检测胰腺癌细胞系和患者组织中 TRIM31 的蛋白和 mRNA 表达。采用免疫组织化学法分析 89 例人胰腺癌组织样本，以研究 TRIM31 表达与胰腺癌患者临床病理特征之间的关系。采用 MTT、FACS 和 Tunel 分析等功能分析方法，确定 TRIM31 在人胰腺癌进展中的致癌作用。此外，还使用 Western blot 和荧光素酶测定法来确定 TRIM31 促进胰腺癌细胞化疗耐药的机制。TRIM31 在胰腺癌细胞系和组织中的表达明显上调，并且高 TRIM31 表达与胰腺癌患者侵袭性表型和不良预后相关。TRIM31 过表达赋予胰腺癌细胞对吉西他滨的耐药性；然而，抑制 TRIM31 可使胰腺癌细胞系对吉西他滨的细胞毒性作用敏感。此外，TRIM31 通过促进肿瘤坏死因子受体相关因子 2（TRAF2）的 K63 连接多泛素化来上调核 p65 的水平，并在胰腺癌细胞中持续激活核转录因子 kappa B（NF-κB）。我们的研究结果提供了证据表明，TRIM31 是胰腺癌患者的一个潜在治疗靶点。靶向 TRIM31 信号可能是增强胰腺癌化疗耐药期间吉西他滨反应的一种有前途的策略。
