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Published on: November 29, 2016
Distinct transcriptional programs of SOX2 in different types of small cell lung cancers
Yuki Tenjin1,2, Kumi Matsuura3, Shinji Kudoh1
1Department of Pathology and Experimental Medicine, Graduate School of Medical Science, Kumamoto University, Honjo 1-1-1, Chuo-ku, Kumamoto, 860-8556, Japan.
Abstract:
SOX2 is recognized as an oncogene in human small cell lung cancer (SCLC), which is an aggressive neuroendocrine (NE) tumor. However, the role of SOX2 in SCLC is not completely understood, and strategies to selectively target SOX2 in SCLC cells remain elusive. Here, we show, using next-generation sequencing, that SOX2 expressed in the ASCL1-high SCLC (SCLC-A) subtype cell line is dependent on ASCL1, which is a lineage-specific transcriptional factor, and is involved in NE differentiation and tumorigenesis. ASCL1 recruits SOX2, which promotes INSM1 and WNT11 expression. Immunohistochemical studies revealed that SCLC tissue samples expressed SOX2, ASCL1, and INSM1 in 18 out of the 30 cases (60%). Contrary to the ASCL1-SOX2 signaling axis controlling SCLC biology in the SCLC-A subtype, SOX2 targets distinct genes such as those related to the Hippo pathway in the ASCL1-negative, YAP1-high SCLC (SCLC-Y) subtype. Although SOX2 knockdown experiments suppressed NE differentiation and cell proliferation in the SCLC-A subtype, they did not sufficiently impair the growth of the SCLC-Y subtype cell lines in vitro and ex vivo. The present results support the importance of the ASCL1-SOX2 axis as a main subtype of SCLC, and suggest the therapeutic potential of targeting the ASCL1-SOX2 axis.
Insights
SOX2 is an oncogene in small cell lung cancer (SCLC). Targeting the ASCL1-SOX2 axis shows therapeutic potential in the SCLC-A subtype, but not SCLC-Y.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- SOX2 is an oncogene in small cell lung cancer (SCLC), an aggressive neuroendocrine tumor.
- The precise role of SOX2 and targeted therapeutic strategies in SCLC remain incompletely understood.
Purpose of the Study:
- To elucidate the role of SOX2 in different SCLC subtypes.
- To investigate the ASCL1-SOX2 signaling axis and its therapeutic implications.
Main Methods:
- Next-generation sequencing to analyze SOX2 dependency on ASCL1 in SCLC-A.
- Immunohistochemistry to assess SOX2, ASCL1, and INSM1 expression in SCLC tissues.
- SOX2 knockdown experiments in SCLC-A and SCLC-Y subtypes.
Main Results:
- SOX2 expression in SCLC-A is ASCL1-dependent, promoting NE differentiation and tumorigenesis via INSM1 and WNT11.
- SOX2 targets Hippo pathway genes in the ASCL1-negative SCLC-Y subtype.
- SOX2 knockdown inhibited SCLC-A proliferation but had limited effect on SCLC-Y growth.
Conclusions:
- The ASCL1-SOX2 axis is crucial for the SCLC-A subtype.
- SOX2 plays distinct roles in SCLC-A and SCLC-Y subtypes.
- Targeting the ASCL1-SOX2 axis presents a potential therapeutic strategy for SCLC-A.
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