MiR-221 targets QKI to enhance the tumorigenic capacity of human colorectal cancer stem cells

Junko Mukohyama, Taichi Isobe, Qingjiang Hu, Takanori Hayashi, Takashi Watanabe, Masao Maeda, Hisano Yanagi, Xin Qian, Kimihiro Yamashita, Hironobu Minami, Koshi Mimori, Debashis Sahoo, Yoshihiro Kakeji, Akira Suzuki, Piero Dalerba, Yohei Shimono

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Abstract

Mirnas are key players in the integrated regulation of cellular processes and shape many of the functional properties that define the "cancer stem cell" (CSC) phenotype. Little is known, however, about miRNAs that regulate such properties in human colorectal carcinoma. In this study, we compared the expression levels of 754 miRNAs between paired samples of EpCAMþ/CD44þ cancer cells (enriched in CSCs) and EpCAMþ/CD44neg cancer cells (with CSC depletion) sorted in parallel from human primary colorectal carcinomas and identified miR-221 as the miRNA that displayed the highest level of preferential expression in EpCAMþ/CD44þ cancer cells. High levels of miR-221 expression were associated with Lgr5þ cells in mouse colon crypts and reduced survival in patients with colorectal carcinoma. Constitutive overexpression of miR-221 enhanced organoid-forming capacity of both conventional colorectal carcinoma cell lines and patient-derived xenografts (PDX) in vitro. Importantly, constitutive downregulation of miR-221 suppressed organoid-forming capacity in vitro and substantially reduced the tumorigenic capacity of CSC populations from PDX lines in vivo. Finally, the most abundant splicing isoform of the human Quaking (QKI) gene, QKI-5, was identified as a functional target of miR-221; overexpression of miR-221-reduced QKI-5 protein levels in human colorectal carcinoma cells. As expected, overexpression of QKI-5 suppressed organoid-forming capacity in vitro and tumorigenic capacity of colorectal carcinoma PDX cells in vivo. Our study reveals a mechanistic link between miR-221 and QKI and highlights their key role in regulating CSC properties in human colorectal cancer.

Original languageEnglish
Pages (from-to)5151-5158
Number of pages8
JournalCancer Research
Volume79
Issue number20
DOIs
Publication statusPublished - Oct 15 2019

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Neoplastic Stem Cells
Colorectal Neoplasms
Organoids
MicroRNAs
Heterografts
Neoplasms
Protein Isoforms
Colon
Down-Regulation
Phenotype
Cell Line
Survival
Population
Genes
Epithelial Cell Adhesion Molecule
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Mukohyama, J., Isobe, T., Hu, Q., Hayashi, T., Watanabe, T., Maeda, M., ... Shimono, Y. (2019). MiR-221 targets QKI to enhance the tumorigenic capacity of human colorectal cancer stem cells. Cancer Research, 79(20), 5151-5158. https://doi.org/10.1158/0008-5472.CAN-18-3544

MiR-221 targets QKI to enhance the tumorigenic capacity of human colorectal cancer stem cells. / Mukohyama, Junko; Isobe, Taichi; Hu, Qingjiang; Hayashi, Takanori; Watanabe, Takashi; Maeda, Masao; Yanagi, Hisano; Qian, Xin; Yamashita, Kimihiro; Minami, Hironobu; Mimori, Koshi; Sahoo, Debashis; Kakeji, Yoshihiro; Suzuki, Akira; Dalerba, Piero; Shimono, Yohei.

In: Cancer Research, Vol. 79, No. 20, 15.10.2019, p. 5151-5158.

Research output: Contribution to journalArticle

Mukohyama, J, Isobe, T, Hu, Q, Hayashi, T, Watanabe, T, Maeda, M, Yanagi, H, Qian, X, Yamashita, K, Minami, H, Mimori, K, Sahoo, D, Kakeji, Y, Suzuki, A, Dalerba, P & Shimono, Y 2019, 'MiR-221 targets QKI to enhance the tumorigenic capacity of human colorectal cancer stem cells', Cancer Research, vol. 79, no. 20, pp. 5151-5158. https://doi.org/10.1158/0008-5472.CAN-18-3544
Mukohyama, Junko ; Isobe, Taichi ; Hu, Qingjiang ; Hayashi, Takanori ; Watanabe, Takashi ; Maeda, Masao ; Yanagi, Hisano ; Qian, Xin ; Yamashita, Kimihiro ; Minami, Hironobu ; Mimori, Koshi ; Sahoo, Debashis ; Kakeji, Yoshihiro ; Suzuki, Akira ; Dalerba, Piero ; Shimono, Yohei. / MiR-221 targets QKI to enhance the tumorigenic capacity of human colorectal cancer stem cells. In: Cancer Research. 2019 ; Vol. 79, No. 20. pp. 5151-5158.
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AU - Mukohyama, Junko

AU - Isobe, Taichi

AU - Hu, Qingjiang

AU - Hayashi, Takanori

AU - Watanabe, Takashi

AU - Maeda, Masao

AU - Yanagi, Hisano

AU - Qian, Xin

AU - Yamashita, Kimihiro

AU - Minami, Hironobu

AU - Mimori, Koshi

AU - Sahoo, Debashis

AU - Kakeji, Yoshihiro

AU - Suzuki, Akira

AU - Dalerba, Piero

AU - Shimono, Yohei

PY - 2019/10/15

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N2 - Mirnas are key players in the integrated regulation of cellular processes and shape many of the functional properties that define the "cancer stem cell" (CSC) phenotype. Little is known, however, about miRNAs that regulate such properties in human colorectal carcinoma. In this study, we compared the expression levels of 754 miRNAs between paired samples of EpCAMþ/CD44þ cancer cells (enriched in CSCs) and EpCAMþ/CD44neg cancer cells (with CSC depletion) sorted in parallel from human primary colorectal carcinomas and identified miR-221 as the miRNA that displayed the highest level of preferential expression in EpCAMþ/CD44þ cancer cells. High levels of miR-221 expression were associated with Lgr5þ cells in mouse colon crypts and reduced survival in patients with colorectal carcinoma. Constitutive overexpression of miR-221 enhanced organoid-forming capacity of both conventional colorectal carcinoma cell lines and patient-derived xenografts (PDX) in vitro. Importantly, constitutive downregulation of miR-221 suppressed organoid-forming capacity in vitro and substantially reduced the tumorigenic capacity of CSC populations from PDX lines in vivo. Finally, the most abundant splicing isoform of the human Quaking (QKI) gene, QKI-5, was identified as a functional target of miR-221; overexpression of miR-221-reduced QKI-5 protein levels in human colorectal carcinoma cells. As expected, overexpression of QKI-5 suppressed organoid-forming capacity in vitro and tumorigenic capacity of colorectal carcinoma PDX cells in vivo. Our study reveals a mechanistic link between miR-221 and QKI and highlights their key role in regulating CSC properties in human colorectal cancer.

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