Role of cancer stem cells in racial disparity in colorectal cancer

Abstract

Although African‐Americans (AAs) have a higher incidence of colorectal cancer (CRC) than White people, the underlying biochemical mechanisms for this increase are poorly understood. The current investigation was undertaken to examine whether differences in self‐renewing cancer stem/stem‐like cells (CSCs) in the colonic mucosa, whose stemness is regulated by certain microRNAs (miRs), could partly be responsible for the racial disparity in CRC. The study contains 53 AAs and 47 White people. We found the number of adenomas and the proportion of CD44+ CD166− CSC phenotype in the colon to be significantly higher in AAs than White people. MicroRNAs profile in CSC‐enriched colonic mucosal cells, expressed as ratio of high‐risk (≥3 adenomas) to low‐risk (no adenoma) CRC patients revealed an 8‐fold increase in miR‐1207‐5p in AAs, compared to a 1.2‐fold increase of the same in White people. This increase in AA was associated with a marked rise in lncRNA PVT1 (plasmacytoma variant translocation 1), a host gene of miR‐1207‐5p. Forced expression of miR‐1207‐5p in normal human colonic epithelial cells HCoEpiC and CCD841 produced an increase in stemness, as evidenced by morphologically elongated epithelial mesenchymal transition( EMT) phenotype and significant increases in CSC markers (CD44, CD166, and CD133) as well as TGF‐β, CTNNB1, MMP2, Slug, Snail, and Vimentin, and reduction in Twist and N‐Cadherin. Our findings suggest that an increase in CSCs, specifically the CD44+ CD166− phenotype in the colon could be a predisposing factor for the increased incidence of CRC among AAs. MicroRNA 1207‐5p appears to play a crucial role in regulating stemness in colonic epithelial cells in AAs.

PVT1 Long Non-coding RNA in Gastrointestinal Cancer

“…All these observations have been extended to human cancer cell lines. Precisely, CACO2, SW480, SW620, HT29, and HCT116 cells derived from human colorectal tumors displayed higher levels of total PVT1 compared to NCM460, FHC and HCoEpiC normal colonic epithelial cells (67,70,72,81). Likewise, AGS, MKN45, SGC7901, and BGC823 gastric cancer cell lines have higher PVT1 expression compared to GES1 normal gastric epithelium cell line (76,79).…”

“…The role of PVT1-encoded miRNAs in the initiation and/or progression of malignancies in the stomach or colon is uncertain due to the lack of literature. Only miR-1207 is reported to have an effect in gastric cancer proliferation and invasion, or in the stemness properties of colon cancer cells (52,81). Specifically, it has been shown how ectopic expression of miR-1207-5p in the SGC7901 gastric tumor cell line is able to reduce proliferation and invasion in vitro and in vivo by targeting the catalytic subunit of the telomerase complex hTERT (52).…”

“…Aberrant expression of hTERT is associated with the metastatic ability of gastric tumors (114,115). In turn, miR-1207-5p overexpression in the HCoEpiC normal colon epithelial cell line enables the formation of primary and secondary spheres by a mechanism involving the upregulation at the mRNA level of TGFβ, CTNNB1, MMP2 and several colorectal stem cell markers such as CD44, CD133, and CD166 (81). Consistent with the tight relationship between stemness and epithelial-mesenchymal transition (EMT), Slug, Snail, and vimentin were also found upregulated (81,116) (Figure 2).…”

Epigenetic basis of cancer health disparities: Looking beyond genetic differences

“…Another study with colorectal cancer patients (53 AA and 47 CA), not only found an evidence of miRNAs, but also of cancer stem cells and long noncoding RNA PVT1, the host for miR-1207-5p, in cancer racial disparity. AA patients had significantly high levels of miR-1207-5p, which was mechanistically linked to increased ‘stemness’, as evidenced by increase in various markers of cancer stem cells and EMT [151]. This increase in cancer stem cells can possibly explain the relatively aggressive colorectal cancers in AA patients.…”

Lidamycin decreases CD133 expression in hepatocellular carcinoma via the Notch signaling pathway

“…CSCs may lead to recurrence, drug-resistance and tumor formation in HCC (5). Cluster of differentiation (CD)133 is a membrane-bound pentaspan glycoprotein that has been identified as a surface biomarker in a variety of cancer types, including breast, colon, prostate, pancreatic, lung and liver carcinoma (2,3,(6)(7)(8)(9)(10)(11). Although its function remains unclear, directly targeting CD133 has been demonstrated to be a potentially effective strategy for eliminating CSCs (11,12).…”