TGF-β-mediated epithelial–mesenchymal transition and tumor-promoting effects in CMT64 cells are reflected in the transcriptomic signature of human lung adenocarcinoma

Abstract

Epithelial–mesenchymal transition (EMT) is a cellular process during which epithelial cells acquire mesenchymal phenotypes. Cancer cells undergo EMT to acquire malignant features and TGF-β is a key regulator of EMT. Here, we demonstrate for the first time that TGF-β could elicit EMT in a mouse lung adenocarcinoma cell line. TGF-β signaling activation led to cell morphological changes corresponding to EMT and enhanced the expression of mesenchymal markers and EMT-associated transcription factors in CMT64 lung cancer cells. RNA-sequencing analyses revealed that TGF-β increases expression of Tead transcription factors and an array of Tead2 target genes. TGF-β stimulation also resulted in alternative splicing of several genes including Cd44, tight junction protein 1 (Tjp1), and Cortactin (Cttn). In parallel with EMT, TGF-β enhanced cell growth of CMT64 cells and promoted tumor formation in a syngeneic transplantation model. Of clinical importance, the expression of TGF-β-induced genes identified in CMT64 cells correlated with EMT gene signatures in human lung adenocarcinoma tissue samples. Furthermore, TGF-β-induced gene enrichment was related to poor prognosis, underscoring the tumor-promoting role of TGF-β signaling in lung adenocarcinoma. Our cellular and syngeneic transplantation model would provide a simple and useful experimental tool to study the significance of TGF-β signaling and EMT.

Slit2/Robo1 signaling inhibits small‐cell lung cancer by targeting β‐catenin signaling in tumor cells and macrophages

“…In contrast, Slit2 overexpression increased E‐cadherin levels, suppressing EMT. Tgf‐β1 is a master regulator of the EMT in cancer cells and has been linked to EMT phenotype in a plethora of tumor types [ 78 , 79 ]. In addition, Tgf‐β1 signaling has been shown to Robo1 expression in mammary epithelial cells [ 59 ], suggesting that the Slit2 binding of Robo1 may inhibit the EMT transition of SCLC by suppressing Tgf‐β1 signaling.…”

Liquid Biopsy in non-small cell lung cancer: exosomes as a tool for the study of biomarkers.

“…In relation to these exosomes-enriched pathways, a study published in 2021 highlights the association between LUAD patients and TGF-β levels. High TGF-β-mediated EMT expression were associated with shorter survival and were predictive of poor prognosis in lung adenocarcinoma [270].…”