Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, People's Republic of China.
School of Public Health, Xinxiang Medical University, Xinxiang, People's Republic of China.
J Exp Clin Cancer Res. 2019 Aug 30;38(1):319. doi: 10.1186/s13046-019-1316-7.
High rates of recurrence and metastasis are the major cause of the poor outcomes for patients with lung cancer. In previous research, we have demonstrated that Tac2-N promotes tumor growth by suppressing p53 signaling in lung cancer. Beyond that, other biological functions and clinical significance of Tac2-N in lung cancer progression are still unknown.
Tissue microarrays of 272 lung cancer patients were constructed to assess the association of Tac2-N expression and prognosis of lung cancer patients with different clinical stages. The protein expression of Tac2-N in metastatic and non-metastatic specimens were detected by IHC. In vitro migration and invasion and in vivo nude mice metastasis model were used to evaluate the effect of Tac2-N ectopic expression on metastasis capability of lung cancer cells. The downstream signaling pathway of Tac2-N was explored using luciferase reporter assays and WB.
The expression of Tac2-N was associated with advanced stages, but not with early stages (P = 0.513). Tac2-N expression is sharply overexpressed in metastatic tumors compared with non-metastatic tumors. In vitro and in vivo assays suggested that Tac2-N facilitated migration and invasion of lung cancer cells in vitro and promoted tumor metastasis in vivo. Mechanistically, Tac2-N increased the degradation of IκB by promoting its phosphorylation, and subsequently activated NF-κB activity by facilitating the nuclear translocation of NF-κB and stimulating the transcription of targets, MMP7 and MMP9. Notably, the C2B domain of Tac2-N was crucial for Tac2-N to activate NF-κB signal. Blockage of NF-κB by shRNA or inhibitor attenuates the function of Tac2-N in the promotion of metastasis.
Our study provided proof of principle to show that Tac2-N serves as a novel oncogene gene and plays an important role in the progression and metastasis of lung cancer.
肺癌患者的高复发和转移率是其预后不良的主要原因。在之前的研究中，我们已经证明 Tac2-N 通过抑制肺癌中的 p53 信号通路来促进肿瘤生长。除此之外， Tac2-N 在肺癌进展中的其他生物学功能和临床意义尚不清楚。
构建了 272 例肺癌患者的组织微阵列，以评估 Tac2-N 表达与不同临床分期肺癌患者预后的关系。通过免疫组化检测转移性和非转移性标本中 Tac2-N 的蛋白表达。体外迁移和侵袭实验以及体内裸鼠转移模型用于评估 Tac2-N 异位表达对肺癌细胞转移能力的影响。利用荧光素酶报告基因检测和 WB 探讨 Tac2-N 的下游信号通路。
Tac2-N 的表达与晚期有关，与早期无关（P=0.513）。与非转移性肿瘤相比，转移性肿瘤中 Tac2-N 的表达明显过表达。体外和体内实验表明， Tac2-N 促进了肺癌细胞的迁移和侵袭，并促进了体内肿瘤的转移。机制上， Tac2-N 通过促进 IκB 的磷酸化使其降解，从而激活 NF-κB 活性，促进 NF-κB 核转位，并刺激 MMP7 和 MMP9 等靶基因的转录，从而增加了 IκB 的降解。值得注意的是， Tac2-N 的 C2B 结构域对于 Tac2-N 激活 NF-κB 信号至关重要。通过 shRNA 或抑制剂阻断 NF-κB 可减弱 Tac2-N 促进转移的功能。
本研究提供了原理性证据，表明 Tac2-N 是一种新的癌基因，在肺癌的进展和转移中发挥重要作用。
