TGIF2 promotes the progression of lung adenocarcinoma by bridging EGFR/RAS/ERK signaling to cancer cell stemness

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.

miR-541 serves as a prognostic biomarker of osteosarcoma and its regulatory effect on tumor cell proliferation, migration and invasion by targeting TGIF2

“…TGIF2 has been identified as an oncogene in some cancers, such as lung adenocarcinoma [30] and glioma [31]. In OS, TGIF2 has also been reported to be involved in tumor progression [32].…”

CCL16 maintains stem cell-like properties in breast cancer by activating CCR2/GSK3β/β-catenin/OCT4 axis

“…We identified several novel candidate genes (e.g., ICAM3, CCL16, PDE3A, and PRTN3) and showed that ICAM3 mediates cancer cell stemness as well as cancer-related inflammation via Src/PI3K/AKT signaling 18 . In addition, we showed that the PDE3A gene maintains cancer cell stemness and may therefore serve as a target in breast cancer therapy 22 . In this study, we observed that CCL16 (a potential cancer stemness gene) is overexpressed in breast tumors and significantly correlates with clinical progression.…”

“…Protein expression was detected by western blot carried out according to protocols described previously 22 , 23 . Primary antibodies used in this assay are listed in Table S2 .…”

MYLK4 promotes tumor progression through the activation of epidermal growth factor receptor signaling in osteosarcoma

“…In diabetic nephropathy, Chen et al showed that EGFR transactivation was crucial for TGFβ/Smad3 activation and renal fibrosis [ 38 ]. In lung adenocarcinoma, Du et al found that TGF-β-induced factor homeobox 2 mediated the EGFR-RAS-ERK signaling pathway to enhance the stemness of cancer cells [ 39 ]. In live cancer, TGF-β could upregulate the expression of EGFR ligands, which transactivated the EGFR pathway, counteracting its pro-apoptotic response [ 40 ].…”