Distinct transcriptional programs of SOX2 in different types of small cell lung cancers.

Autor: Tenjin Y; Department of Pathology and Experimental Medicine, Graduate School of Medical Science, Kumamoto University, Honjo 1-1-1, Chuo-ku, Kumamoto, 860-8556, Japan.; Department of Respiratory Medicine, Graduate School of Medical Science, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 1-1-1, Chuo-ku, Kumamoto, 860-8556, Japan., Matsuura K; Department of Pluripotent Stem Cell Biology, Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto, 860-0811, Japan., Kudoh S; Department of Pathology and Experimental Medicine, Graduate School of Medical Science, Kumamoto University, Honjo 1-1-1, Chuo-ku, Kumamoto, 860-8556, Japan., Usuki S; Liaison Laboratory Research Promotion Center (LILA), Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto, 860-0811, Japan., Yamada T; Department of Pathology and Experimental Medicine, Graduate School of Medical Science, Kumamoto University, Honjo 1-1-1, Chuo-ku, Kumamoto, 860-8556, Japan.; Department of Thoracic Surgery, Graduate School of Medical Science, Kumamoto University, Honjo 1-1-1, Chuo-ku, Kumamoto, 860-8556, Japan., Matsuo A; Department of Pathology and Experimental Medicine, Graduate School of Medical Science, Kumamoto University, Honjo 1-1-1, Chuo-ku, Kumamoto, 860-8556, Japan., Sato Y; Department of Pathology and Experimental Medicine, Graduate School of Medical Science, Kumamoto University, Honjo 1-1-1, Chuo-ku, Kumamoto, 860-8556, Japan., Saito H; Department of Pathology and Experimental Medicine, Graduate School of Medical Science, Kumamoto University, Honjo 1-1-1, Chuo-ku, Kumamoto, 860-8556, Japan.; Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kumamoto University, Honjo 1-1-1, Chuo-ku, Kumamoto, 860-8556, Japan., Fujino K; Department of Pathology and Experimental Medicine, Graduate School of Medical Science, Kumamoto University, Honjo 1-1-1, Chuo-ku, Kumamoto, 860-8556, Japan.; Department of Thoracic Surgery, Graduate School of Medical Science, Kumamoto University, Honjo 1-1-1, Chuo-ku, Kumamoto, 860-8556, Japan., Wakimoto J; Division of Pathology, Minami Kyushu National Hospital, Kagoshima, 899-5293, Japan., Ichimura T; Department of Pathology, Faculty of Medicine, Saitama Medical University, Saitama, 350-0495, Japan., Kohrogi H; Department of Respiratory Medicine, Omuta Tenryo Hospital, Tenryo 1-100, Omuta, Fukuoka, 836-8556, Japan., Sakagami T; Department of Respiratory Medicine, Graduate School of Medical Science, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 1-1-1, Chuo-ku, Kumamoto, 860-8556, Japan., Niwa H; Department of Pluripotent Stem Cell Biology, Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto, 860-0811, Japan., Ito T; Department of Pathology and Experimental Medicine, Graduate School of Medical Science, Kumamoto University, Honjo 1-1-1, Chuo-ku, Kumamoto, 860-8556, Japan. takaito@kumamoto-u.ac.jp.
Jazyk: angličtina
Zdroj: Laboratory investigation; a journal of technical methods and pathology [Lab Invest] 2020 Dec; Vol. 100 (12), pp. 1575-1588. Date of Electronic Publication: 2020 Aug 14.
DOI: 10.1038/s41374-020-00479-0
Abstrakt: 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.
Databáze: MEDLINE
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