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Significance of achaete-scute complex homologue 1 (ASCL1) in pulmonary neuroendocrine carcinomas; RNA sequence analyses using small cell lung cancer cells and Ascl1-induced pulmonary neuroendocrine carcinoma cells

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Abstract

ASCL1 is one of the master transcription factors of small cell lung carcinoma (SCLC). To investigate the significance of ASCL1 in pulmonary neuroendocrine carcinoma, we performed 2 comparative RNA-seq studies between H69 (ASCL1-positive, classical type SCLC) and H69AR (ASCL1-negative, variant type SCLC) and between ASCL1-transfected A549 adenocarcinoma cell lines (A549(ASCL1+) cell lines) and A549(control) cell lines. RNA-seq analyses revealed that 940 genes were significantly different between the H69 and H69AR cell lines, and 728 between the A549(ASCL1+) and A549(control) cell lines. In total, 120 common genes between these analyses were selected as candidate ASCL1-related genes, and included genes with various cellular functions, such as neural development, secretion, growth, and morphology. Their expression degrees in three classical and two variant SCLC cell lines, two A549(ASCL1+) and two A549(control) cell lines were subjected to quantitative PCR analyses. Since the candidate ASCL1-related genes were strongly expressed in the classical SCLC and A549(ASCL1+) cell lines and more weakly expressed in the variant SCLC and A549(control) cell lines, the ASCL1-related 7 molecules INSM1, ISL1, SYT4, KCTD16, SEZ6, MS4A8, and COBL were further selected. These molecules suggested diverse functions for A549(ASCL1+): INSM1 and ISL1 are transcription factors associated with neuroendocrine differentiation, while SYT4, KTCD16, and SEZ6 may be related to neurosecretory functions and MS4A8 and COBL to cell growth and morphology. An immunohistochemistry of these seven molecules was performed on lung carcinoma tissues and the xenotransplanted tumors of A549(ASCL1+), and they were preferentially and positively stained in ASCL1-postive tumor tissues.

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Abbreviations

ASCL1:

Achaete-scute complex homologue 1

HES1:

Hairy and enhancer of split 1

CHGA:

Chromogranin A

CHGB:

Chromogranin B

SCG2:

Secretogranin 2

SYP:

Synaptophysin

NCAM:

Neural cell adhesion molecule

GRP:

Gastrin releasing peptide,

SYT1:

Synaptotagmin1

INSM1:

Insulinoma associated protein 1

SNAP25:

Synaptosome associated protein 25

YAP1:

Yes associated protein 1

NEUROD1:

Neurogenic differentiation 1

POU2F3:

POU class 2 homeobox 3

CPLX2:

Complexin 2

SYTL3:

Synaptotagmin like 3

NTRK3:

Neurotrophic receptor tyrosine kinase 3

NCF2:

Neutrophil cytosolic factor 2

GAS2:

Growth arrest specific 2

CCND2:

Cyclin D2

INHBB:

Inhibin subunit beta B

CREG1:

Cellular repressor of E1A stimulated genes 1

PLK2:

Polo-like kinase 2

CCND3:

Cyclin D3

CLDN4:

Claudin 4

BCAM:

Basal cell adhesion molecule

JUP:

Junction plakoglobin

CDH1:

Cadherin 1

CD44:

CD44 molecule

CLMP:

CXADR like membrane protein

ISL1:

Islet1

SYT4:

Synaptotagmin4

KCTD16:

Potassium channel tetramerization domain containing 16

SEZ6:

Seizure-related 6 homolog

MS4A8:

Membrane spanning 4 domains A8

COBL:

Cordon-bleu WH2 repeat protein

BDNF:

Brain derived neurotrophic factor

NFASC:

Neurofascin

DMD:

Dystrophin

GDNF:

Glial cell derived neurotrophic factor

VCAN:

Versican

ABCC4:

ATP binding cassette subfamily C member 4

ABCC8:

ATP binding cassette subfamily C member 8

SLC30A3:

Solute carrier family 30 member 3

SLC39A6:

Solute carrier family 39 member 6

SLC40A1:

Solute carrier family 40 member 1

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Acknowledgments

We thank Ms. Takako Maeda for her technical assistance and Mr. Shingo Usuki and the staff of the LILA of the Institute of Molecular Embryology and Genetics, Kumamoto University for their technical support of the RNA-seq analysis. This study was supported in part by the program of the Joint Usage/Research Center for Developmental Medicine, Institute of Molecular Embryology and Genetics, Kumamoto University, by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (18K19480), by a Grant from the Smoking Research Foundation, and by an endowment from Dr. Yuko Aihara of Aihara Allergy and Pediatric Clinic.

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  1. Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan

    Shinji Kudoh, Yuki Tenjin, Tatsuya Yamada, Akira Matsuo, Noritaka Kudo, Younosuke Sato & Takaaki Ito

  2. Department of Pathology, Kumamoto Health Science University, Kumamoto, Japan

    Hiroki Kameyama

  3. Department of Pathology, Faculty of Medicine, Saitama Medical University, Saitama, Japan

    Takaya Ichimura

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  1. Shinji Kudoh
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Kudoh, S., Tenjin, Y., Kameyama, H. et al. Significance of achaete-scute complex homologue 1 (ASCL1) in pulmonary neuroendocrine carcinomas; RNA sequence analyses using small cell lung cancer cells and Ascl1-induced pulmonary neuroendocrine carcinoma cells. Histochem Cell Biol 153, 443–456 (2020). https://doi.org/10.1007/s00418-020-01863-z

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