Abstract
TGF-β-induced factor homeobox 2 (TGIF2) is a transcription regulator that plays essential roles in the regulation of development and cell fate decisions. Aberrant expression of TGIF family proteins has been observed in several cancers, including ovarian, esophageal, and colorectal cancers. Here, we report that TGIF2 mediates the EGFR–RAS–ERK signaling pathway to enhance the stemness of lung adenocarcinoma (LUAD) cells and, therefore, promote the progression and metastasis of LUAD. We found that high TGIF2 expression was closely correlated with tumor growth, lymph node metastasis, and survival of patients with LUAD. Mice bearing TGIF2-silenced H1299 xenografts developed smaller tumors and fewer lung metastases. Importantly, silencing TGIF2 decreased the cancer stem cell (CSC)-like properties in A549 and H1299 cells. Furthermore, we identified that TGIF2 binding to the OCT4 promoter promotes its expression. In both LUAD cells and in vivo LUAD mouse models, we revealed that EGFR–RAS–ERK signaling phosphorylated TGIF2 and increased its stability, which was important for TGIF2-promoted LUAD stemness since phosphorylation-deficient TGIF2 mutants lost these functions. Thus, our study revealed that an important factor, TGIF2, bridges EGFR signaling to the CSC characteristics of LUAD cells, which can be utilized as an effective target for LUAD therapy.
Highlights
Lung cancer is the leading cause of cancer-related death worldwide, and non-small cell lung cancer (NSCLC) accounts for approximately 85% of all types of lung cancers.[1]
lung adenocarcinoma (LUAD) cancer stem cell (CSC)-like cells were reported to highly express CD133 and CD44.26,27 We found that knocking down TGF-β-induced factor homeobox 2 (TGIF2) significantly reduced the CD133+ CD44+ subpopulation, which could be rescued by ectopically expressed TGIF2 as well regulator bridging EGF receptor (EGFR) signaling to the stemness of LUAD cells (Fig. 2i)
TGIF2AA did not increase the side population of DISCUSSION In this study, we found that TGIF2 phosphorylation triggered by EGFR/RAS/ERK signaling enhanced the stability of TGIF2 to promote OCT4 transcription, resulting in increased stemness and metastasis of LUAD cells (Fig. 6j)
Summary
Lung cancer is the leading cause of cancer-related death worldwide, and non-small cell lung cancer (NSCLC) accounts for approximately 85% of all types of lung cancers.[1]. We demonstrated that TGIF2 phosphorylation induced by EGFR/RAS/ERK signaling promotes OCT4 expression, leading to increased stemness and metastasis of LUAD cells. We observed decreased side reporter driven by the OCT4 promoter (Fig. S2b), suggesting that populations of TGIF2-silenced H1299 and A549 cells, which in human lung cancer cells, TGIF1 was not able to regulate OCT4, Fig. 1 Upregulation of TGIF2 in LUADs and its association with prognosis. EGF/EGFR–RAS–ERK signaling increases the stability of TGIF2 to promote the CSC-like characteristics of LUAD cells To further understand whether phosphorylation of TGIF2 by EGFR–RAS–ERK is important for EGFR promoted stemness of cancer cells, we compared the functions of wild type-TGIF2 (TGIF2WT) and phosphorylation-deficient TGIF2 mutants (i.e., T182A and T186A, or TGIF2AA for short, Fig. 5k) in promoting the stemness of LUAD cells.
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