Transcriptional control of a collagen deposition and adhesion process that promotes lung adenocarcinoma growth and metastasis
Xiaochao Tan, Priyam Banerjee, Xin Liu, Jiang Yu, Sieun Lee, Young-Ho Ahn, Chad J. Creighton, Jonathan M. Kurie
Xiaochao Tan, Priyam Banerjee, Xin Liu, Jiang Yu, Sieun Lee, Young-Ho Ahn, Chad J. Creighton, Jonathan M. Kurie
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Research Article Oncology

Transcriptional control of a collagen deposition and adhesion process that promotes lung adenocarcinoma growth and metastasis

Abstract

A fibrotic stroma accumulates in advanced cancers, and invasive cancer cells migrate along collagen fibers that facilitate dissemination from the primary tumor. However, the ways in which tumor cells govern these processes remain unclear. Here, we report that the epithelial-mesenchymal transition–activating transcription factor ZEB1 increased type I collagen (Col1) secretion and enhanced tumor cell adherence to Col1. Mechanistically, ZEB1 increased the levels of α1β1 integrin (encoded by Itga1 and Itgb1) by inhibiting PP2A activity, which reduced nuclear accumulation of HDAC4 and, thereby, derepressed Itga1 gene transcription. In parallel, ZEB1 relieved the miRNA-148a-mediated silencing of Itga1. High levels of Itga1 enhanced tumor cell adherence to Col1 and were essential for Col1-induced tumor growth and metastasis. Furthermore, ZEB1 enhanced Col1 secretion by increasing the expression of a kinesin protein that facilitated transport and secretion of Col1-containing vesicles. Our findings elucidate a transcriptional mechanism by which lung adenocarcinoma cells coordinate a collagen deposition and adhesion process that facilitates tumor progression.

Authors

Xiaochao Tan, Priyam Banerjee, Xin Liu, Jiang Yu, Sieun Lee, Young-Ho Ahn, Chad J. Creighton, Jonathan M. Kurie

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Figure 1

Epithelial-mesenchymal transition increases tumor cell adherence to collagen through α1β1 integrin.

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Epithelial-mesenchymal transition increases tumor cell adherence to coll...
(A) Cell adherence was quantified 1 hour after the indicated KP cells were seeded on wells coated with collagen 1 (Col1), collagen IV (Col4), fibronectin, BSA, or nothing, and OD595 values are shown in the heatmap. E, epithelial; M, mesenchymal. n = 4. (B) Cell spreading assay on Col1. Cells were plated in Col1-coated plates for 1 hour, and percentages of spread cells were quantified. Scale bar: 50 μm. (C) Quantitative reverse transcription PCR analysis of the mRNA levels of ZEB1 and Col1 receptors in KP cell lines (Pearson correlation). (D) Western blot analysis of Itga1 and Itgb1 in KP cell lines classified as epithelial or mesenchymal. β-Actin was used as a loading control. (E) Heatmap illustration of gene expression levels in lung adenocarcinoma and squamous cell carcinoma data sets (n = 1016 tumors) in The Cancer Genome Atlas. An epithelial-mesenchymal transition score was correlated with the levels of collagen receptors using the Pearson coefficient (r value). (F) Cell adherence was quantified 1 hour or 2 hours after the indicated cells were seeded on uncoated wells or on wells coated with Col1. n = 4. **P < 0.01. (G) Cell spreading assay on Col1. Percentages of spread cells were quantified. Scale bar: 100 μm. ***P < 0.001. (H) Quantitative reverse transcription PCR analysis of Col1 receptors. (I) Western blot analysis of Itga1 in 393P_Vec and 393P_ZEB1 cells. Data are shown as the mean ± SEM from a single experiment incorporating biological replicate samples (n = 3, unless otherwise indicated) and are representative of at least 2 independent experiments. *P < 0.01; ***P < 0.001. Two-tailed Student’s t test.