title: Overexpression of PER3 Inhibits Self-Renewal Capability and Chemoresistance of Colorectal Cancer Stem-Like Cells via Inhibition of Notch and β-Catenin Signaling.
abstract: PER3, a circadian clock gene, plays an important role in colorectal cancer, but its action and underlying mechanism in colorectal cancer stem-like cells (CSCs) remain unclear. In this study, the colorectal CSCs were enriched in colorectal HCT-116 sphere-forming cells, expressing lower levels of stem cell markers CD133, CD44, LGR5, and SOX2 compared with HCT-116 cells. A drug-resistant strain from HCT-116 was established. Western blot and qRT-PCR analysis showed that PER3 was downregulated in colorectal CSCs and drug-resistant HCT-116. Overexpression of PER3 could strengthen 5-FU-induced inhibitory effects on colorectal CSCs, but knockdown of PER3 decreased its inhibition of colorectal CSCs. In addition, overexpression of PER3 in colorectal CSCs resulted in reduced colony formation efficiency in a soft agar medium and self-renewal efficiency. Inversely, knockdown of PER3 enhanced self-renewal of colorectal CSCs. Overexpression of PER3 decreased stemness markers and Notch1, Jagged1, β-catenin, c-Myc, and LGR5 in colorectal CSCs. When Notch or β-catenin signaling was inhibited, the chemoresistance and self-renewal capability of colorectal CSCs were decreased. It was confirmed that PER3 can reduce chemoresistance and self-renewal capability of colorectal CSCs via inhibition of Notch and β-catenin signaling. Our results reveal that PER3 plays a critical role in maintaining the stemness of colorectal CSCs and may be a promising target for elimination of CSCs.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.forename: Sai
authors.initials: S
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Yang
authors.forename: Guogang
authors.initials: G
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Su
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015870:Gene Expression; D045325:HCT116 Cells; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D056950:Period Circadian Proteins / Q000235:genetics*; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C512644:PER3 protein, human; D056950:Period Circadian Proteins; D051880:Receptors, Notch; D051176:beta Catenin