HMGA2–FOXL2 Axis Regulates Metastases and Epithelial-to-Mesenchymal Transition of Chemoresistant Gastric Cancer

Abstract

Purpose: Chemoresistance is the main cause of treatment failure in cancer and is associated with distant metastases and epithelial-tomesenchymal transition (EMT). This study was aimed to explore the mechanism of metastases and EMT in chemoresistant gastric cancer.Experimental Design: A key molecular pathway was identified via gene profiling and a bioinformatic analysis in a chemoresistant gastric cancer model. The roles of FOXL2, HMGA2, and ITGA2 were validated via loss-of-function and gain-of-function experiments in vitro and in an orthotopic gastric cancer animal model. The regulation of FOXL2 by HMGA2 was explored via immunoprecipitation and luciferase reporter assays. The expression of these proteins in gastric cancer tissues was examined by IHC.Results: HMGA2 and FOXL2 directly regulated the metastasis and EMT of chemoresistant gastric cancer. The interaction between HMGA2 and pRb facilitated the transactivation of FOXL2 by E2F1, and ITGA2 was the downstream effector of the HMGA2-FOXL2 pathway. HMGA2, FOXL2, and ITGA2 were associated with the TNM classification and staging of gastric cancer and were increased in metastatic lymph nodes and distant metastases. Increased HMGA2, FOXL2, and ITGA2 levels were associated with reduced overall survival periods of patients with gastric cancer.Conclusions: This study demonstrated that the transactivation of FOXL2 driven by interactions between HMGA2 and pRb might exert critical effects on the metastases and EMT of chemoresistant gastric cancer. Blocking the HMGA2-FOXL2-ITGA2 pathway could serve as a new strategy for gastric cancer treatment.

TiHo-0906: a new feline mammary cancer cell line with molecular, morphological, and immunocytological characteristics of epithelial to mesenchymal transition

“…HMGA2 elicits EMT by activating a series of transcription factors 24,25 , while CD44 participates in the downregulation of E-cad commonly observed during EMT 12,28 . Immunohistochemically, there were no specific cross-reactivity of the HMGA2 selected antibody with feline tissue.…”

“…Consequently, it has been induced in cell culture by different methods 13,14,22,23 . The High-mobility group AT-hook 2 protein (HMGA2) activates a range of EMT transcription factors implicated in the repression of epithelial genes, and mesenchymal genes up-regulation 24,25 . Therefore, EMT-derived cells are usually characterized by a higher HMGA2 expression 9,26 , loss or reduced expression of E-cadherin (E-cad), up-regulation of vimentin (Vim) 7,9 , and co-expression of epithelial markers (cytokeratins [CKs]) and mesenchymal markers (calponin [CALP], smooth muscle actin [SMA], and Vim) 7,27 .…”

High G2 and S‐phase expressed 1 expression promotes acral melanoma progression and correlates with poor clinical prognosis

“…Integrins are involved in the regulation of cell motility, migration, and invasion . ITGA2, mainly together with the β1 integrin subunit, has also been reported in many cancers . ITGA2 regulation by miRNAs and epigenetic modifications is crucial for invasion, metastasis and EMT .…”

“…44 ITGA2, mainly together with the b1 integrin subunit, has also been reported in many cancers. [45][46][47][48][49] ITGA2 regulation by miRNAs and epigenetic modifications is crucial for invasion, metastasis and EMT. [50][51][52][53] Therefore, we explored the contribution of ITGA2 in siGTSE1-mediated cell AM migration and invasion.…”

LncRNA ZEB1‐AS1 down‐regulation suppresses the proliferation and invasion by inhibiting ZEB1 expression in oesophageal squamous cell carcinoma

“…Immunohistochemistry assay was carried out according to previous document . Briefly, tumour tissues with paraffin embedding were serially cut with 4 μm, and the sections were dewaxed and rehydrated according to standard protocol.…”