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 2

ZEB1 increases tumor cell adherence to Col1 through α1β1 integrin.

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ZEB1 increases tumor cell adherence to Col1 through α1β1 integrin. (A) W...
(A) Western blot analysis of Itga1 in 393P_ZEB1 cells transfected with Itga1 shRNAs (shItga1) or control shRNA (shCTL). (B) Cell adhesion to Col1 or plastic (no coating) at indicated time points. n = 4. *P = 0.01; ***P < 0.001. (C) Percentages of spread cells on collagen at indicated time points. ***P < 0.001. (D) Western blot analysis of Itga1 in 393P cells transfected with Itga1 expression vector or control vector (Vec). (E) Cell adhesion to Col1 or plastic at indicated time points. n = 4. *P = 0.03; **P = 0.005. (F) Percentages of spread cells on Col1 at indicated time points. ***P < 0.001. (G–I) Cell adhesion to collagen or plastic. H1299 cells transfected with ITGA1 shRNA or control shRNA (shCTL) and Itga1 expression vector or empty vector (Vec) (G), 344SQ cells transfected with shRNA against Itgb1 or control shRNA and siRNA against Itga1 or control siRNA (siCTL; H), and 393P cells transfected with Iga1 expression vector or control vector and siRNA against Itgb1 or siCTL (I) are shown. n = 4. **P < 0.01; ***P < 0.001. (J) Schema showing tail vein injection of red fluorescent protein–labeled (RFP-labeled) 344SQ cells into mice. (K) Percentage of RFP-positive cells in mouse lungs at 4 hours after injection. (L) Green fluorescent protein–labeled (GFP-labeled) and RFP-labeled 344SQ transfectants were coinjected into mice and the resulting micrometastases were imaged and quantified. 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. Two-tailed Student’s t test for 2-group comparisons; 1-way ANOVA test for multiple comparisons.