Forkhead-box A3 (FOXA3) Represses Cancer Stemness and Partially Potentiates Chemosensitivity by Targeting Metastasis-Associated in Colon Cancer 1 (MACC1) Signaling Pathway in Colorectal Cancer Cells

Abstract

Background: The major challenge to the treatment of advanced colorectal cancer (CRC) is persistent occurrence of chemoresistance. One of the established etiologies is the existence of cancerstem-like cells (CSCs) using which tumors resist to external therapeutic challenges. Objective: The forkhead-box A3 (FOXA3) is a potent transcription factor that potentiates the acquisition and maintenance of stemness fate in many physiological systems. However, its effect on cancer stemness, particularly treatment, has not been explored in CRC, forming the basis of the current study. Methods: FOXA3 expression in oxaliplatin-resistant CRC tissues and cells was evaluated using RT-qPCR. Effects of FOXA3 manipulation on sensitivity to oxaliplatin were assessed using WST-1, apoptotic ELISA, colony formation and xenograft model. Effects of FOXA3 alteration on CSCs were determined using tumor sphere assay and CD44 staining. Transcriptional regulation of MACC1 by FOXA3 was studied using ChIP, Co-IP and luciferase reporter assay. Results: FOXA3 expression was significantly reduced in tumor samples from oxaliplatin-non-responsive patients compared with that in tumor samples from oxaliplatin-sensitive patients. This downregulation of FOXA3 expression predicted a poor post-chemotherapy overall- or disease-free survival in our 117-patient cohort. FOXA3 down-regulation significantly enhanced cell survival and stem-like properties, thus rendering the CRC cells unresponsiveness to oxaliplatin-induced cell death. Mechanistically, the anti-neoplasic effect of FOXA3 was mediated mainly through transcriptional repression of metastasis-associated in colon cancer 1 (MACC1) in oxaliplatin-resistant CRC cells. Conclusion: Our findings establish FOXA3 as a potent tumor suppressor in CRC, which may disrupt the maintenance of stemness and modulate sensitivity to oxaliplatin by inhibiting the transcription of MACC1 within CRC cells.

LncRNA FGD5-AS1 Facilitates the Radioresistance of Breast Cancer Cells by Enhancing MACC1 Expression Through Competitively Sponging miR-497-5p

“…This phenotype could be rescued by exogenous MACC1 expression or miR-497 depletion, which robustly suggested that they are connected in a loop. Besides, previous studies have reported that MACC1 exerts an inhibitory effect on drug resistance (60). As reported, FGD5-AS1 deficiency can promote chemoresistance via triggering the PI3K pathway, Wnt/b-catenin et al (41,42,45).…”

MACC1 Regulates LGR5 to Promote Cancer Stem Cell Properties in Colorectal Cancer

“…In general, MACC1 has already been described in the stemness context in different cancer entities. In CRC, this association was analyzed in several studies [27][28][29][30], demonstrating the involvement of FoxA3, miR-3163 and DCLK1 able to phosphorylate MACC1. Targeting MACC1 in CRC not only affects known MACC1-induced features such as migration and invasion, but also influences stemness-associated phenotypes.…”

Suppression of Cell Tumorigenicity by Non-neural Pro-differentiation Factors via Inhibition of Neural Property in Tumorigenic Cells

“…FOXA3 expression in cancers has not been clear. However, FOXA3 was demonstrated to repress stemness of colorectal cancer cells via targeting MACC1 ( Li N. et al, 2020 ), whose gene expression is enriched in neural cells during early embryogenesis ( Melvin et al, 2013 ). Foxa3 can promote anterior neural tissue formation during zebrafish embryogenesis.…”