Background: The major challenge to the treatment of advanced colorectal cancer (CRC)
is the persistent occurrence of chemoresistance. One of the established etiologies is the existence of
cancer stem-like cells (CSCs), due to which, tumors show resistance 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
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 tumorsphere 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-neoplastic effect of FOXA3 was mediated mainly through transcriptional
repression of metastasis-associated in colon cancer 1 (MACC1) in oxaliplatin-resistant
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.