Metallothionein 2A Expression in Cancer-Associated Fibroblasts and Cancer Cells Promotes Esophageal Squamous Cell Carcinoma Progression

Abstract

Esophageal cancer has the sixth highest mortality rate worldwide. Cancer-associated fibroblasts (CAFs) are involved in the progression of various cancers. Previously, we demonstrated an association between high expression of the CAF marker, fibroblast activation protein, and poor prognosis of esophageal squamous cell carcinoma (ESCC). We also established CAF-like cells by indirect co-culture of bone marrow-derived mesenchymal stem cells with ESCC cell lines and found metallothionein 2A (MT2A) to be highly expressed in them. Here, to explore the function of MT2A in CAFs, we silenced MT2A in the CAF-like cells and ESCC cell lines using small interfering RNA. MT2A knockdown in the CAF-like cells suppressed expression and secretion of insulin-like growth factor binding protein 2 (IGFBP2); recombinant IGFBP2 promoted migration and invasiveness of ESCC cells via NFκB, Akt, and Erk signaling pathways. Furthermore, MT2A knockdown in the ESCC cell lines inhibited their growth, migration, and invasiveness. Immunohistochemistry demonstrated that high MT2A expression in the cancer stroma and cancer nest of ESCC tissues correlated with poor prognosis of ESCC patients. Hence, we report that MT2A in CAFs and cancer cells contributes to ESCC progression. MT2A and IGFBP2 are potential novel therapeutic targets in ESCC.

Single cell sequencing revealed the mechanism of PD-1 resistance affected by the expression profile of peripheral blood immune cells in ESCC

“…A Japanese researcher found that MT2A was highly expressed in CAF cells constructed by them. Knockdown of MT2A inhibited the expression and secretion of insulin-like growth factor binding protein 2 (IGFBP2), and recombinant IGFBP2 promoted the migration and invasion of ESCC cells through NF-κB, Akt and Erk signaling pathways ( 57 ). The opposite effect of MTs in different tumors may be related to tumor type and differentiation, other environmental stimuli or gene mutations ( 13 ).…”

High MT2A Expression Predicts Worse Prognosis in Patients with Urothelial Carcinoma

“…Silencing of MT2A-inhibited cell growth by inducing cell cycle arrest in the G1-phase (G1-arrest) involving the ATM/Chk2/cdc25A pathway [21]. In esophageal cancer, high immunoexpression of MT2A is associated with a high pathological stage, lymph node metastasis, and lymphovascular invasion [22]. In vitro, MT2A knockdown in cancer cells (TE-10 and TE-11) inhibited the malignant phenotype by increasing E-cadherin expression.…”

The Role of Tumor Microenvironment in Invasion and Metastasis of Esophageal Squamous Cell Carcinoma

“…IL-6 secreted by FAP + CAFs not only can promote ESCC cell invasion and EMT but also can recruit FoxP3 + T cells and induce TAM M2 polarization to promote metastasis ( 81 , 82 ). The presence of CAFs in ESCC patients is associated with increased micro-vessel density, TAMs, and EMT, which are critical for ESCC invasion and metastasis ( 83 , 84 ). A number of genes have been shown to promote ESCC invasion and metastasis via the CAF transformation and EMT process ( 85 , 86 ).…”