The emerging role of SOX2 in cell proliferation and survival and its crosstalk with oncogenic signaling in lung cancer.
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.
Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.
Yu-Ting
YT
Chou
Chih-Chan
CC
Lee
Shih-Hsin
SH
Hsiao
Sey-En
SE
Lin
Sheng-Chieh
SC
Lin
Chih-Hung
CH
Chung
Chi-Hsiu
CH
Chung
Yu-Rong
YR
Kao
Yuan-Hung
YH
Wang
Chien-Tsun
CT
Chen
Yau-Huei
YH
Wei
Cheng-Wen
CW
Wu
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D017239:Paclitaxel / Q000494:pharmacology; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis; D051020:bcl-X Protein / Q000378:metabolism
C494811:BCL2L1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D051020:bcl-X Protein; C512478:EGFR protein, human; D066246:ErbB Receptors; D017239:Paclitaxel; D002945:Cisplatin
Apoptosis; Autophagy; Cancer stem cells; Lung cancer; Oncogenic pathway; Stem cell signaling