Abstract 3089: Study of HOX genes in the stem cell origin of CRC

Abstract

Abstract Our goal is to ascertain how HOX-regulatory mechanisms play a role in the SC origin of colorectal cancer (CRC). While HOX genes encode master regulatory transcription factors that regulate stem cells (SCs), their role in cancer etiology is under-studied. We and others find that HOX genes are aberrantly expressed in CRC. We previously reported that HOXA4 and HOXD10 along with aldehyde dehydrogenase (ALDH) and the other components of the retinoic acid (RA) signaling pathway are selectively expressed in human colon SCs. That RA signaling regulates HOX expression indicates that RA regulation of HOX gene expression mainly occurs through ALDH+ SCs in the colon. We hypothesize that specific HOX genes regulate growth and differentiation of SCs in human colon and HOX gene dysregulation leads to decreased differentiation and SC overpopulation. Indeed, our bioinformatics analysis shows that many HOX genes are overexpressed in CRCs, which parallels the overpopulation of ALDH+ SC that occurs during CRC tumorigenesis. We are using immunohistochemical mapping to measure proportions of SCs and HOX-positive cells in normal and malignant human colon tissues. We find that specific HOX proteins have increased expression levels in malignant colon tissues. In addition, immunofluorescence co-staining of human colon tissues is used to validate HOX gene expression in ALDH+ SCs. We are also evaluating the effects of all-trans-RA (ATRA) on HOX gene expression and on cellular proliferation and differentiation using CRC cell lines. Our results show that ATRA treatment of HT29 CRC cells leads to reduced proliferation and decreased expression of select HOX genes. These results indicate that HOX genes like HOXA4, HOXA9, and HOXD10, are expressed colonic SCs, and are regulated by RA signaling. Overall, the overexpression of HOX genes in cancer SCs appears to contribute to the SC origin of CRC. Citation Format: Brian Osmond, Caroline O. Facey, Lynn M. Opdenaker, Bruce M. Boman. Study of HOX genes in the stem cell origin of CRC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3089.