ATOH1 Can Regulate the Tumorigenicity of Gastric Cancer Cells by Inducing the Differentiation of Cancer Stem Cells

Myoung-Eun Han; Su-Jin Baek; Seon-Young Kim; Chi-Dug Kang; Sae-Ock Oh

doi:10.1371/journal.pone.0126085

ATOH1 Can Regulate the Tumorigenicity of Gastric Cancer Cells by Inducing the Differentiation of Cancer Stem Cells

PLoS One. 2015 May 7;10(5):e0126085. doi: 10.1371/journal.pone.0126085. eCollection 2015.

Authors

Myoung-Eun Han¹, Su-Jin Baek², Seon-Young Kim³, Chi-Dug Kang³, Sae-Ock Oh⁴

Affiliations

¹ Department of Anatomy, School of Medicine, Pusan National University, Pusan, Republic of Korea; Medical Research Center for Ischemic Tissue Regeneration, Pusan National University, Pusan, Republic of Korea.
² Medical Genomics Research Center, KRIBB, Daejeon, Republic of Korea.
³ Department of Biochemistry, School of Medicine, Pusan National University, Pusan, Republic of Korea.
⁴ Department of Anatomy, School of Medicine, Pusan National University, Pusan, Republic of Korea.

Abstract

Cancer stem cells (CSCs) have been shown to mediate tumorigenicity, chemo-resistance, radio-resistance and metastasis, which suggest they be considered therapeutic targets. Because their differentiated daughter cells are no longer tumorigenic, to induce the differentiation of CSCs can be one of strategies which can eradicate CSCs. Here we show that ATOH1 can induce the differentiation of gastric cancer stem cells (GCSCs). Real time PCR and western blot analysis showed that ATOH1 was induced during the differentiation of GCSCs. Furthermore, the lentivirus-induced overexpression of ATOH1 in GCSCs and in gastric cancer cell lines significantly induced differentiation, reduced proliferation and sphere formation, and reduced in vivo tumor formation in the subcutaneous injection and liver metastasis xenograft models. These results suggest ATOH1 be considered for the development of a differentiation therapy for gastric cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Basic Helix-Loop-Helix Transcription Factors / genetics
Basic Helix-Loop-Helix Transcription Factors / metabolism*
Carcinogenesis / genetics
Carcinogenesis / metabolism
Carcinogenesis / pathology*
Cell Differentiation
Cell Line, Tumor
Gastric Mucosa / metabolism
Gene Expression Regulation, Neoplastic
Humans
Mice, SCID
Neoplastic Stem Cells / cytology
Neoplastic Stem Cells / metabolism*
Neoplastic Stem Cells / pathology*
Promoter Regions, Genetic
Signal Transduction
Stomach / pathology*
Stomach Neoplasms / genetics
Stomach Neoplasms / metabolism
Stomach Neoplasms / pathology*
Tumor Cells, Cultured
Tumor Suppressor Proteins / genetics
Up-Regulation

Substances

ATOH1 protein, human
Basic Helix-Loop-Helix Transcription Factors
RASSF4 protein, human
Tumor Suppressor Proteins

Associated data

GEO/GSE46597

Grants and funding

This work was supported by the Bio and Medical Technology Development Program (2012M3A9C6050213) and Basic Science Research Foundation (2012R1A1A3010521) of the National Research Foundation (NRF) funded by the Korean government (MEST) and, a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (0920050). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.