Insulinoma-Associated Protein 1 Is a Crucial Regulator of Neuroendocrine Differentiation in Lung Cancer.
Insulinoma-associated protein 1 (INSM1) is expressed exclusively in embryonic developing neuroendocrine (NE) tissues. INSM1 gene expression is specific for small-cell lung cancer (SCLC), along with achaete-scute homolog-like 1 (ASCL1) and several NE molecules, such as chromogranin A, synaptophysin, and neural cell adhesion molecule 1. However, the underlying biological role of INSM1 in lung cancer remains largely unknown. We first showed that surgically resected SCLC samples specifically expressed INSM1. Forced expression of the INSM1 gene in adenocarcinoma cell lines (H358 and H1975) induced the expression of ASCL1, brain-2 (BRN2), chromogranin A, synaptophysin, and neural cell adhesion molecule 1; in contrast, knockdown of the INSM1 gene by siRNA in SCLC (H69 and H889) decreased their expression. However, forced/knockdown expression of ASCL1 and BRN2 did not affect INSM1 expression. A chromatin immunoprecipitation study revealed that INSM1 bound to the promoter region of the ASCL1 gene. A xenotransplantation assay using tet-on INSM1 gene-transfected adenocarcinoma cell lines demonstrated that INSM1 induced NE differentiation and growth inhibition. Furthermore, we found that INSM1 was not expressed in non-small-cell lung cancer and some SCLC cell lines expressing Notch1-Hes1. By forced/knockdown expression of Notch1 or Hes1 genes, we revealed that Notch1-Hes1 signaling suppressed INSM1, as well as ASCL1 and BRN2. INSM1, expressed exclusively in SCLC, is a crucial regulator of NE differentiation in SCLCs, and is regulated by the Notch1-Hes1 signaling pathway.
Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Kosuke
K
Fujino
Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Yamato
Y
Motooka
Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Pathology, Faculty of Medicine, Suez Canal University, Ismaileya, Egypt.
Wael A
WA
Hassan
Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan; Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismaileya, Egypt.
Mohamed O
MO
Ali Abdalla
Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Yonosuke
Y
Sato
Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Shinji
S
Kudoh
Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Koki
K
Hasegawa
Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Kanako
K
Niimori-Kita
Department of Thoracic Surgery, National Hospital Organization Kumamoto Saishunso Hospital, Kumamoto, Japan.
Hironori
H
Kobayashi
Department of Thoracic Surgery and Pathology, National Hospital Organization Minami-Kyushu Hospital, Kagoshima, Japan.
Ichiro
I
Kubota
Department of Thoracic Surgery and Pathology, National Hospital Organization Minami-Kyushu Hospital, Kagoshima, Japan.
Joeji
J
Wakimoto
Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Makoto
M
Suzuki
Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Electronic address: takaito@kumamoto-u.ac.jp.
Takaaki
T
Ito
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D055785:Gene Knockdown Techniques; D064593:Heterografts; D018398:Homeodomain Proteins / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008815:Mice, Inbred Strains; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009368:Neoplasm Transplantation; D055099:Neuroendocrine Cells / Q000378:metabolism / Q000473:pathology*; D050809:POU Domain Factors / Q000378:metabolism / Q000502:physiology; D051881:Receptor, Notch1 / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D055752:Small Cell Lung Carcinoma / Q000378:metabolism* / Q000473:pathology; D000072056:Transcription Factor HES-1
D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D009363:Neoplasm Proteins; D050809:POU Domain Factors; D051881:Receptor, Notch1; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; C065500:ASCL1 protein, human; C497761:NOTCH1 protein, human; C085076:transcription factor Brn-2; C087342:INSM1 protein, human; C078493:HES1 protein, human