The emerging role of SOX2 in cell proliferation and survival and its crosstalk with oncogenic signaling in lung cancer

Yu Ting Chou, Chih Chan Lee, Shih Hsin Hsiao, Sey En Lin, Sheng Chieh Lin, Chih Hung Chung, Chi Hsiu Chung, Yu Rong Kao, Yuan Hung Wang, Chien Tsun Chen, Yau Huei Wei, Cheng Wen Wu

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Tumor cells have long been observed to share several biological characteristics with normal stem/progenitor cells; however, the oncogenic mechanisms underlying the lung stem/progenitor cell signaling remain elusive. Here, we report that SOX2, a self-renewal factor in lung stem/progenitor cells, is highly expressed in a subclass of lung cancer cells, the proliferation, survival, and chemoresistance of which are dependent on SOX2 signaling. Overexpression of SOX2 promotes oncogenic phenotypes in lung cancer cells; knockdown of SOX2 attenuated cell proliferation. We observed that SOX2 increased the expression of epidermal growth factor receptor (EGFR), and EGFR activation further upregulated SOX2 levels, forming a positive feedback loop. SOX2 expression promoted chemoresistance, and silencing of SOX2 perturbed mitochondrial function, causing marked apoptosis and autophagy. SOX2 induced BCL2L1, the ectopic expression of which rescued the effects of SOX2 silencing on apoptosis, autophagy, and mitochondrial function. SOX2 promoted tumor formation, along with increased cell proliferation in a xenograft mouse model. SOX2 expression is associated with poor prognosis in lung cancer patients; moreover, SOX2, EGFR, and BCL2L1 expression levels were significantly correlated in lung tumors. Our findings support the emerging role of SOX2 in cell proliferation and survival by eliciting oncogenic EGFR and BCL2L1 signaling with potential applications as a prognosis marker and a therapeutic target in lung cancer.

Original languageEnglish
Pages (from-to)2607-2619
Number of pages13
JournalStem Cells
Volume31
Issue number12
DOIs
Publication statusPublished - Dec 2013

Fingerprint

Lung Neoplasms
Cell Survival
Stem Cells
Cell Proliferation
Epidermal Growth Factor Receptor
Autophagy
Lung
Apoptosis
Neoplasms
Heterografts
Phenotype
Therapeutics

Keywords

  • Apoptosis
  • Autophagy
  • Cancer stem cells
  • Lung cancer
  • Oncogenic pathway
  • Stem cell signaling

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine
  • Medicine(all)

Cite this

The emerging role of SOX2 in cell proliferation and survival and its crosstalk with oncogenic signaling in lung cancer. / Chou, Yu Ting; Lee, Chih Chan; Hsiao, Shih Hsin; Lin, Sey En; Lin, Sheng Chieh; Chung, Chih Hung; Chung, Chi Hsiu; Kao, Yu Rong; Wang, Yuan Hung; Chen, Chien Tsun; Wei, Yau Huei; Wu, Cheng Wen.

In: Stem Cells, Vol. 31, No. 12, 12.2013, p. 2607-2619.

Research output: Contribution to journalArticle

Chou, YT, Lee, CC, Hsiao, SH, Lin, SE, Lin, SC, Chung, CH, Chung, CH, Kao, YR, Wang, YH, Chen, CT, Wei, YH & Wu, CW 2013, 'The emerging role of SOX2 in cell proliferation and survival and its crosstalk with oncogenic signaling in lung cancer', Stem Cells, vol. 31, no. 12, pp. 2607-2619. https://doi.org/10.1002/stem.1518
Chou, Yu Ting ; Lee, Chih Chan ; Hsiao, Shih Hsin ; Lin, Sey En ; Lin, Sheng Chieh ; Chung, Chih Hung ; Chung, Chi Hsiu ; Kao, Yu Rong ; Wang, Yuan Hung ; Chen, Chien Tsun ; Wei, Yau Huei ; Wu, Cheng Wen. / The emerging role of SOX2 in cell proliferation and survival and its crosstalk with oncogenic signaling in lung cancer. In: Stem Cells. 2013 ; Vol. 31, No. 12. pp. 2607-2619.
@article{5d77c88ab7514279972958f64653d6cd,
title = "The emerging role of SOX2 in cell proliferation and survival and its crosstalk with oncogenic signaling in lung cancer",
abstract = "Tumor cells have long been observed to share several biological characteristics with normal stem/progenitor cells; however, the oncogenic mechanisms underlying the lung stem/progenitor cell signaling remain elusive. Here, we report that SOX2, a self-renewal factor in lung stem/progenitor cells, is highly expressed in a subclass of lung cancer cells, the proliferation, survival, and chemoresistance of which are dependent on SOX2 signaling. Overexpression of SOX2 promotes oncogenic phenotypes in lung cancer cells; knockdown of SOX2 attenuated cell proliferation. We observed that SOX2 increased the expression of epidermal growth factor receptor (EGFR), and EGFR activation further upregulated SOX2 levels, forming a positive feedback loop. SOX2 expression promoted chemoresistance, and silencing of SOX2 perturbed mitochondrial function, causing marked apoptosis and autophagy. SOX2 induced BCL2L1, the ectopic expression of which rescued the effects of SOX2 silencing on apoptosis, autophagy, and mitochondrial function. SOX2 promoted tumor formation, along with increased cell proliferation in a xenograft mouse model. SOX2 expression is associated with poor prognosis in lung cancer patients; moreover, SOX2, EGFR, and BCL2L1 expression levels were significantly correlated in lung tumors. Our findings support the emerging role of SOX2 in cell proliferation and survival by eliciting oncogenic EGFR and BCL2L1 signaling with potential applications as a prognosis marker and a therapeutic target in lung cancer.",
keywords = "Apoptosis, Autophagy, Cancer stem cells, Lung cancer, Oncogenic pathway, Stem cell signaling",
author = "Chou, {Yu Ting} and Lee, {Chih Chan} and Hsiao, {Shih Hsin} and Lin, {Sey En} and Lin, {Sheng Chieh} and Chung, {Chih Hung} and Chung, {Chi Hsiu} and Kao, {Yu Rong} and Wang, {Yuan Hung} and Chen, {Chien Tsun} and Wei, {Yau Huei} and Wu, {Cheng Wen}",
year = "2013",
month = "12",
doi = "10.1002/stem.1518",
language = "English",
volume = "31",
pages = "2607--2619",
journal = "Stem Cells",
issn = "1066-5099",
publisher = "AlphaMed Press",
number = "12",

}

TY - JOUR

T1 - The emerging role of SOX2 in cell proliferation and survival and its crosstalk with oncogenic signaling in lung cancer

AU - Chou, Yu Ting

AU - Lee, Chih Chan

AU - Hsiao, Shih Hsin

AU - Lin, Sey En

AU - Lin, Sheng Chieh

AU - Chung, Chih Hung

AU - Chung, Chi Hsiu

AU - Kao, Yu Rong

AU - Wang, Yuan Hung

AU - Chen, Chien Tsun

AU - Wei, Yau Huei

AU - Wu, Cheng Wen

PY - 2013/12

Y1 - 2013/12

N2 - Tumor cells have long been observed to share several biological characteristics with normal stem/progenitor cells; however, the oncogenic mechanisms underlying the lung stem/progenitor cell signaling remain elusive. Here, we report that SOX2, a self-renewal factor in lung stem/progenitor cells, is highly expressed in a subclass of lung cancer cells, the proliferation, survival, and chemoresistance of which are dependent on SOX2 signaling. Overexpression of SOX2 promotes oncogenic phenotypes in lung cancer cells; knockdown of SOX2 attenuated cell proliferation. We observed that SOX2 increased the expression of epidermal growth factor receptor (EGFR), and EGFR activation further upregulated SOX2 levels, forming a positive feedback loop. SOX2 expression promoted chemoresistance, and silencing of SOX2 perturbed mitochondrial function, causing marked apoptosis and autophagy. SOX2 induced BCL2L1, the ectopic expression of which rescued the effects of SOX2 silencing on apoptosis, autophagy, and mitochondrial function. SOX2 promoted tumor formation, along with increased cell proliferation in a xenograft mouse model. SOX2 expression is associated with poor prognosis in lung cancer patients; moreover, SOX2, EGFR, and BCL2L1 expression levels were significantly correlated in lung tumors. Our findings support the emerging role of SOX2 in cell proliferation and survival by eliciting oncogenic EGFR and BCL2L1 signaling with potential applications as a prognosis marker and a therapeutic target in lung cancer.

AB - Tumor cells have long been observed to share several biological characteristics with normal stem/progenitor cells; however, the oncogenic mechanisms underlying the lung stem/progenitor cell signaling remain elusive. Here, we report that SOX2, a self-renewal factor in lung stem/progenitor cells, is highly expressed in a subclass of lung cancer cells, the proliferation, survival, and chemoresistance of which are dependent on SOX2 signaling. Overexpression of SOX2 promotes oncogenic phenotypes in lung cancer cells; knockdown of SOX2 attenuated cell proliferation. We observed that SOX2 increased the expression of epidermal growth factor receptor (EGFR), and EGFR activation further upregulated SOX2 levels, forming a positive feedback loop. SOX2 expression promoted chemoresistance, and silencing of SOX2 perturbed mitochondrial function, causing marked apoptosis and autophagy. SOX2 induced BCL2L1, the ectopic expression of which rescued the effects of SOX2 silencing on apoptosis, autophagy, and mitochondrial function. SOX2 promoted tumor formation, along with increased cell proliferation in a xenograft mouse model. SOX2 expression is associated with poor prognosis in lung cancer patients; moreover, SOX2, EGFR, and BCL2L1 expression levels were significantly correlated in lung tumors. Our findings support the emerging role of SOX2 in cell proliferation and survival by eliciting oncogenic EGFR and BCL2L1 signaling with potential applications as a prognosis marker and a therapeutic target in lung cancer.

KW - Apoptosis

KW - Autophagy

KW - Cancer stem cells

KW - Lung cancer

KW - Oncogenic pathway

KW - Stem cell signaling

UR - http://www.scopus.com/inward/record.url?scp=84887796196&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887796196&partnerID=8YFLogxK

U2 - 10.1002/stem.1518

DO - 10.1002/stem.1518

M3 - Article

C2 - 23940081

AN - SCOPUS:84887796196

VL - 31

SP - 2607

EP - 2619

JO - Stem Cells

JF - Stem Cells

SN - 1066-5099

IS - 12

ER -