Ascl1-induced Wnt11 regulates neuroendocrine differentiation, cell proliferation, and E-cadherin expression in small-cell lung cancer and Wnt11 regulates small-cell lung cancer biology

The involvement of Wnt signaling in human lung cancer remains unclear. This study investigated the role of Wnt11 in neuroendocrine (NE) differentiation, cell proliferation, and epithelial-to-mesenchymal transition (EMT) in human small-cell lung cancer (SCLC). Immunohistochemical staining of resected...

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Veröffentlicht in:Laboratory investigation 2019-11, Vol.99 (11), p.1622-1635
Hauptverfasser: Tenjin, Yuki, Kudoh, Shinji, Kubota, Sho, Yamada, Tatsuya, Matsuo, Akira, Sato, Younosuke, Ichimura, Takaya, Kohrogi, Hirotsugu, Sashida, Goro, Sakagami, Takuro, Ito, Takaaki
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container_issue 11
container_start_page 1622
container_title Laboratory investigation
container_volume 99
creator Tenjin, Yuki
Kudoh, Shinji
Kubota, Sho
Yamada, Tatsuya
Matsuo, Akira
Sato, Younosuke
Ichimura, Takaya
Kohrogi, Hirotsugu
Sashida, Goro
Sakagami, Takuro
Ito, Takaaki
description The involvement of Wnt signaling in human lung cancer remains unclear. This study investigated the role of Wnt11 in neuroendocrine (NE) differentiation, cell proliferation, and epithelial-to-mesenchymal transition (EMT) in human small-cell lung cancer (SCLC). Immunohistochemical staining of resected specimens showed that Wnt11 was expressed at higher levels in SCLCs than in non-SCLCs; 58.8% of SCLC, 5.2% of adenocarcinoma (ADC), and 23.5% of squamous cell carcinoma tissues stained positive for Wnt11. A positive relationship was observed between Achaete-scute complex homolog 1 (Ascl1) and Wnt11 expression in SCLC cell lines, and this was supported by transcriptome data from SCLC tissue. The expression of Wnt11 and some NE markers increased after the transfection of ASCL1 into the A549 ADC cell line. Knockdown of Ascl1 downregulated Wnt11 expression in SCLC cell lines. Ascl1 regulated Wnt11 expression via lysine H3K27 acetylation at the enhancer region of the WNT11 gene. Wnt11 controlled NE differentiation, cell proliferation, and E-cadherin expression under the regulation of Ascl1 in SCLC cell lines. The phosphorylation of AKT and p38 mitogen-activated protein kinase markedly increased after transfection of WNT11 into the SBC3 SCLC cell line, which suggests that Wnt11 promotes cell proliferation in SCLC cell lines. Ascl1 plays an important role in regulating the Wnt signaling pathway and is one of the driver molecules of Wnt11 in human SCLC. Ascl1 and Wnt11 may employ a cooperative mechanism to control the biology of SCLC. The present results indicate the therapeutic potential of targeting the Ascl1–Wnt11 signaling axis and support the clinical utility of Wnt11 as a biological marker in SCLC.
doi_str_mv 10.1038/s41374-019-0277-y
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This study investigated the role of Wnt11 in neuroendocrine (NE) differentiation, cell proliferation, and epithelial-to-mesenchymal transition (EMT) in human small-cell lung cancer (SCLC). Immunohistochemical staining of resected specimens showed that Wnt11 was expressed at higher levels in SCLCs than in non-SCLCs; 58.8% of SCLC, 5.2% of adenocarcinoma (ADC), and 23.5% of squamous cell carcinoma tissues stained positive for Wnt11. A positive relationship was observed between Achaete-scute complex homolog 1 (Ascl1) and Wnt11 expression in SCLC cell lines, and this was supported by transcriptome data from SCLC tissue. The expression of Wnt11 and some NE markers increased after the transfection of ASCL1 into the A549 ADC cell line. Knockdown of Ascl1 downregulated Wnt11 expression in SCLC cell lines. Ascl1 regulated Wnt11 expression via lysine H3K27 acetylation at the enhancer region of the WNT11 gene. Wnt11 controlled NE differentiation, cell proliferation, and E-cadherin expression under the regulation of Ascl1 in SCLC cell lines. The phosphorylation of AKT and p38 mitogen-activated protein kinase markedly increased after transfection of WNT11 into the SBC3 SCLC cell line, which suggests that Wnt11 promotes cell proliferation in SCLC cell lines. Ascl1 plays an important role in regulating the Wnt signaling pathway and is one of the driver molecules of Wnt11 in human SCLC. Ascl1 and Wnt11 may employ a cooperative mechanism to control the biology of SCLC. 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This study investigated the role of Wnt11 in neuroendocrine (NE) differentiation, cell proliferation, and epithelial-to-mesenchymal transition (EMT) in human small-cell lung cancer (SCLC). Immunohistochemical staining of resected specimens showed that Wnt11 was expressed at higher levels in SCLCs than in non-SCLCs; 58.8% of SCLC, 5.2% of adenocarcinoma (ADC), and 23.5% of squamous cell carcinoma tissues stained positive for Wnt11. A positive relationship was observed between Achaete-scute complex homolog 1 (Ascl1) and Wnt11 expression in SCLC cell lines, and this was supported by transcriptome data from SCLC tissue. The expression of Wnt11 and some NE markers increased after the transfection of ASCL1 into the A549 ADC cell line. Knockdown of Ascl1 downregulated Wnt11 expression in SCLC cell lines. Ascl1 regulated Wnt11 expression via lysine H3K27 acetylation at the enhancer region of the WNT11 gene. Wnt11 controlled NE differentiation, cell proliferation, and E-cadherin expression under the regulation of Ascl1 in SCLC cell lines. The phosphorylation of AKT and p38 mitogen-activated protein kinase markedly increased after transfection of WNT11 into the SBC3 SCLC cell line, which suggests that Wnt11 promotes cell proliferation in SCLC cell lines. Ascl1 plays an important role in regulating the Wnt signaling pathway and is one of the driver molecules of Wnt11 in human SCLC. Ascl1 and Wnt11 may employ a cooperative mechanism to control the biology of SCLC. The present results indicate the therapeutic potential of targeting the Ascl1–Wnt11 signaling axis and support the clinical utility of Wnt11 as a biological marker in SCLC.</description><subject>13/51</subject><subject>13/89</subject><subject>38/1</subject><subject>42/44</subject><subject>45/77</subject><subject>631/67/1612/2143</subject><subject>631/67/395</subject><subject>64/60</subject><subject>Acetylation</subject><subject>Adenocarcinoma</subject><subject>Adenocarcinoma of Lung - genetics</subject><subject>Adenocarcinoma of Lung - metabolism</subject><subject>Adenocarcinoma of Lung - pathology</subject><subject>AKT protein</subject><subject>Animals</subject><subject>Antigens, CD - genetics</subject><subject>Antigens, CD - metabolism</subject><subject>ASCL1 protein</subject><subject>Basic Helix-Loop-Helix Transcription Factors - antagonists &amp; inhibitors</subject><subject>Basic Helix-Loop-Helix Transcription Factors - genetics</subject><subject>Basic Helix-Loop-Helix Transcription Factors - metabolism</subject><subject>Biology</subject><subject>Biomarkers</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Biotechnology</subject><subject>Cadherins - genetics</subject><subject>Cadherins - metabolism</subject><subject>Carcinoma, Squamous Cell - genetics</subject><subject>Carcinoma, Squamous Cell - metabolism</subject><subject>Carcinoma, Squamous Cell - pathology</subject><subject>Cell Differentiation</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Cooperative control</subject><subject>Differentiation</subject><subject>Down-Regulation</subject><subject>E-cadherin</subject><subject>Enhancer Elements, Genetic</subject><subject>Epithelial-Mesenchymal Transition</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene Knockdown Techniques</subject><subject>Heterografts</subject><subject>Histones - metabolism</subject><subject>Homology</subject><subject>Humans</subject><subject>Imides - pharmacology</subject><subject>Kinases</subject><subject>Laboratory Medicine</subject><subject>Lung cancer</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - metabolism</subject><subject>Lung Neoplasms - pathology</subject><subject>Lysine</subject><subject>Male</subject><subject>MAP kinase</subject><subject>Medicine</subject><subject>Medicine &amp; 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Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>Laboratory investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tenjin, Yuki</au><au>Kudoh, Shinji</au><au>Kubota, Sho</au><au>Yamada, Tatsuya</au><au>Matsuo, Akira</au><au>Sato, Younosuke</au><au>Ichimura, Takaya</au><au>Kohrogi, Hirotsugu</au><au>Sashida, Goro</au><au>Sakagami, Takuro</au><au>Ito, Takaaki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ascl1-induced Wnt11 regulates neuroendocrine differentiation, cell proliferation, and E-cadherin expression in small-cell lung cancer and Wnt11 regulates small-cell lung cancer biology</atitle><jtitle>Laboratory investigation</jtitle><stitle>Lab Invest</stitle><addtitle>Lab Invest</addtitle><date>2019-11-01</date><risdate>2019</risdate><volume>99</volume><issue>11</issue><spage>1622</spage><epage>1635</epage><pages>1622-1635</pages><issn>0023-6837</issn><eissn>1530-0307</eissn><abstract>The involvement of Wnt signaling in human lung cancer remains unclear. This study investigated the role of Wnt11 in neuroendocrine (NE) differentiation, cell proliferation, and epithelial-to-mesenchymal transition (EMT) in human small-cell lung cancer (SCLC). Immunohistochemical staining of resected specimens showed that Wnt11 was expressed at higher levels in SCLCs than in non-SCLCs; 58.8% of SCLC, 5.2% of adenocarcinoma (ADC), and 23.5% of squamous cell carcinoma tissues stained positive for Wnt11. A positive relationship was observed between Achaete-scute complex homolog 1 (Ascl1) and Wnt11 expression in SCLC cell lines, and this was supported by transcriptome data from SCLC tissue. The expression of Wnt11 and some NE markers increased after the transfection of ASCL1 into the A549 ADC cell line. Knockdown of Ascl1 downregulated Wnt11 expression in SCLC cell lines. Ascl1 regulated Wnt11 expression via lysine H3K27 acetylation at the enhancer region of the WNT11 gene. Wnt11 controlled NE differentiation, cell proliferation, and E-cadherin expression under the regulation of Ascl1 in SCLC cell lines. The phosphorylation of AKT and p38 mitogen-activated protein kinase markedly increased after transfection of WNT11 into the SBC3 SCLC cell line, which suggests that Wnt11 promotes cell proliferation in SCLC cell lines. Ascl1 plays an important role in regulating the Wnt signaling pathway and is one of the driver molecules of Wnt11 in human SCLC. Ascl1 and Wnt11 may employ a cooperative mechanism to control the biology of SCLC. The present results indicate the therapeutic potential of targeting the Ascl1–Wnt11 signaling axis and support the clinical utility of Wnt11 as a biological marker in SCLC.</abstract><cop>New York</cop><pub>Elsevier Inc</pub><pmid>31231131</pmid><doi>10.1038/s41374-019-0277-y</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0003-2318-5987</orcidid><oa>free_for_read</oa></addata></record>
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identifier ISSN: 0023-6837
ispartof Laboratory investigation, 2019-11, Vol.99 (11), p.1622-1635
issn 0023-6837
1530-0307
language eng
recordid cdi_proquest_miscellaneous_2246241374
source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection
subjects 13/51
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631/67/395
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Acetylation
Adenocarcinoma
Adenocarcinoma of Lung - genetics
Adenocarcinoma of Lung - metabolism
Adenocarcinoma of Lung - pathology
AKT protein
Animals
Antigens, CD - genetics
Antigens, CD - metabolism
ASCL1 protein
Basic Helix-Loop-Helix Transcription Factors - antagonists & inhibitors
Basic Helix-Loop-Helix Transcription Factors - genetics
Basic Helix-Loop-Helix Transcription Factors - metabolism
Biology
Biomarkers
Biomarkers, Tumor - genetics
Biomarkers, Tumor - metabolism
Biotechnology
Cadherins - genetics
Cadherins - metabolism
Carcinoma, Squamous Cell - genetics
Carcinoma, Squamous Cell - metabolism
Carcinoma, Squamous Cell - pathology
Cell Differentiation
Cell growth
Cell Line, Tumor
Cell Proliferation
Cooperative control
Differentiation
Down-Regulation
E-cadherin
Enhancer Elements, Genetic
Epithelial-Mesenchymal Transition
Gene expression
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Heterografts
Histones - metabolism
Homology
Humans
Imides - pharmacology
Kinases
Laboratory Medicine
Lung cancer
Lung Neoplasms - genetics
Lung Neoplasms - metabolism
Lung Neoplasms - pathology
Lysine
Male
MAP kinase
Medicine
Medicine & Public Health
Mesenchyme
Mice
Mice, Knockout
Neuroendocrine Cells - metabolism
Neuroendocrine Cells - pathology
Pathology
Phosphorylation
Protein kinase
Quinolines - pharmacology
RNA, Small Interfering - genetics
Signal transduction
Signaling
Small cell lung carcinoma
Small Cell Lung Carcinoma - genetics
Small Cell Lung Carcinoma - metabolism
Small Cell Lung Carcinoma - pathology
Snail Family Transcription Factors - genetics
Snail Family Transcription Factors - metabolism
Squamous cell carcinoma
Transfection
Wnt protein
Wnt Proteins - antagonists & inhibitors
Wnt Proteins - genetics
Wnt Proteins - metabolism
Wnt Signaling Pathway - drug effects
title Ascl1-induced Wnt11 regulates neuroendocrine differentiation, cell proliferation, and E-cadherin expression in small-cell lung cancer and Wnt11 regulates small-cell lung cancer biology
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