CCT6A suppresses SMAD2 and promotes prometastatic TGF-β signaling
Zhe Ying, … , Jun Li, Mengfeng Li
Zhe Ying, … , Jun Li, Mengfeng Li
Published April 4, 2017
Citation Information: J Clin Invest. 2017;127(5):1725-1740. https://doi.org/10.1172/JCI90439.
View: Text | PDF
Research Article Oncology Article has an altmetric score of 3

CCT6A suppresses SMAD2 and promotes prometastatic TGF-β signaling

Abstract

Paradoxically, during early tumor development in many cancer types, TGF-β acts as a tumor suppressor, whereas in the advanced stages of these cancers, increased TGF-β expression is linked to high metastasis and poor prognosis. These findings suggest that unidentified mechanisms may function to rewire TGF-β signaling toward its prometastatic role in cancer cells. Our current study using non–small-cell lung carcinoma (NSCLC) cell lines, animal models, and clinical specimens demonstrates that suppression of SMAD2, with SMAD3 function intact, switches TGF-β–induced transcriptional responses to a prometastatic state. Importantly, we identified chaperonin containing TCP1 subunit 6A (CCT6A) as an inhibitor and direct binding protein of SMAD2 and found that CCT6A suppresses SMAD2 function in NSCLC cells and promotes metastasis. Furthermore, selective inhibition of SMAD3 or CCT6A efficiently suppresses TGF-β–mediated metastasis. Our findings provide a mechanism that directs TGF-β signaling toward its prometastatic arm and may contribute to the development of therapeutic strategies targeting TGF-β for NSCLC.

Authors

Zhe Ying, Han Tian, Yun Li, Rong Lian, Wei Li, Shanshan Wu, Hui-Zhong Zhang, Jueheng Wu, Lei Liu, Junwei Song, Hongyu Guan, Junchao Cai, Xun Zhu, Jun Li, Mengfeng Li

×

Figure 6

CCT6A mediates TGF-β–promoted metastasis of NSCLC cells.

Options: View larger image (or click on image) Download as PowerPoint
CCT6A mediates TGF-β–promoted metastasis of NSCLC cells. (A–D) Mice were...
(A–D) Mice were intravenously injected via tail vein with the indicated NSCLC cells. Luciferase live-cell imaging (A and C), picric acid staining of metastatic foci, and H&E staining of lung tissue (B and D) revealed that CCT6A promoted survival and metastasis of NSCLC cells with TGF-β expression. Luciferase-labeled images of live mice at different time points following intravenous tail-vein injection of the indicated NSCLC cells are presented in Supplemental Figure 6A. Representative images were from 2 independent experiments, with 6 mice per group in each independent experiment. Scale bars: 100 μm. (E–H) Mice were subcutaneously injected into inguinal folds with the indicated NSCLC cells. Luciferase live-cell imaging (E and G), picric acid staining of metastatic foci, and H&E staining of lung tissue (F and H) showed that silencing CCT6A diminished the metastasis potential of NSCLC cells. Luciferase-labeled images of live mice at different time points following subcutaneous injection into inguinal folds of the indicated NSCLC cells are presented in Supplemental Figure 6L. Representative images were from 2 independent experiments, with 6 mice per group in each independent experiment. Scale bars: 100 μm. (I–K) Tumor sphere formation assays with the indicated NSCLC cells (I and J) and luciferase live-cell images of mice intravenously injected via the tail vein with a low dose (5 × 104) of NSCLC cells (n = 6 per group) on day 30 (J and K) suggested that CCT6A promoted the survival and metastasis of NSCLC cells in a TGF-β signaling–dependent manner. Error bars represent the mean ± SD. **P < 0.01, by Student’s t test.