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

SIMPLE SUMMARY: Cancer-associated fibroblasts (CAFs) are tumor promoters in various cancers. We previously reported a correlation between the high expression of the CAF marker fibroblast activation protein and poor prognosis of esophageal squamous cell carcinoma (ESCC). We also found that metallothionein 2A (MT2A) is highly expressed in CAF-like cells that we established. In the current study, we explored the role of MT2A in ESCC progression. MT2A expression in the CAF-like cells induced expression and secretion of insulin-like growth factor binding protein 2 (IGFBP2), which promoted the migration and invasiveness of ESCC cells through the NFκB, Akt, and Erk signaling pathways. Furthermore, MT2A was involved in ESCC cell growth, migration, and invasiveness. Moreover, high expression of MT2A in the cancer tissue correlated with poor prognosis of ESCC patients. Briefly, we demonstrate that MT2A and IGFBP2 are potential novel therapeutic targets in ESCC. 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.