F-Box/WD Repeat Domain-Containing 7 Induces Chemotherapy Resistance in Colorectal Cancer Stem Cells

Shusaku Honma; Shigeo Hisamori; Aya Nishiuchi; Yoshiro Itatani; Kazutaka Obama; Yohei Shimono; Yoshiharu Sakai

doi:10.3390/cancers11050635

F-Box/WD Repeat Domain-Containing 7 Induces Chemotherapy Resistance in Colorectal Cancer Stem Cells

Cancers (Basel). 2019 May 7;11(5):635. doi: 10.3390/cancers11050635.

Authors

Shusaku Honma¹, Shigeo Hisamori², Aya Nishiuchi³, Yoshiro Itatani⁴, Kazutaka Obama⁵, Yohei Shimono⁶, Yoshiharu Sakai⁷

Affiliations

¹ Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan. [email protected].
² Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan. [email protected].
³ Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan. [email protected].
⁴ Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan. [email protected].
⁵ Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan. [email protected].
⁶ Department of Biochemistry, School of Medicine, Fujita Health University, Aichi 470-1192, Japan. [email protected].
⁷ Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan. [email protected].

Abstract

Although the cancer stem cell (CSC) concept has provided a reasonable explanation for cancer recurrence following chemotherapy, the relationship between CSCs and chemotherapy resistance has not been thoroughly investigated, especially in solid tumors. We aimed to identify the mechanism underlying colorectal cancer (CRC) chemoresistance focusing on the cell cycle mediator F-Box/WD repeat domain-containing 7 (FBXW7). From 55 consecutive CRC cases who underwent neoadjuvant chemotherapy (NAC) or neoadjuvant chemoradiotherapy (NACRT) at Kyoto University Hospital, pre-treatment endoscopic biopsy specimens were collected and divided into two groups upon immunohistochemical (IHC) analysis: 21 cases of FBXW7 high expression (FBXW7-high group) and 34 cases of low expression (FBXW7-low group). High FBXW7 expression in pre-treatment biopsy specimen was significantly associated with poor pathological therapeutic effect (p = 0.019). The proportion of FBXW7-positive cells in surgically resected CRC specimens from patients who underwent NAC or NACRT was significantly higher than that in the pre-treatment biopsy specimens (p < 0.001). The expression of FBXW7 was inversely correlated with that of Ki67 in both pre-treatment biopsy specimens and surgically resected specimens. FBXW7 expression in the EpCAM^high/CD44^high subpopulation isolated by flow cytometry from CRC samples was significantly higher than that in the EpCAM^high/CD44^low subpopulation. Cell-cycle analysis in CRC cell lines revealed that, upon FBXW7 silencing, the proportion of G0/G1 cells was significantly lower than that in control cells. Moreover, knockdown of FBXW7 in CRC cell lines increased the sensitivity to anti-cancer drugs in vitro and in vivo. A subset of CRC stem cells possesses chemoresistance through FBXW7 expression. Cell cycle arrest induced by FBXW7 expression should be considered as a potential therapeutic target to overcome chemoresistance in CRC stem cell subsets.

Keywords: FBXW7; cancer stem cell; cell cycle; chemoresistance; colorectal cancer.