Skip to main content
Top
Published in: Journal of Cancer Research and Clinical Oncology 9/2019

01-09-2019 | NSCLC | Original Article – Cancer Research

Protein expression of close homologue of L1 (CHL1) is a marker for overall survival in non-small cell lung cancer (NSCLC)

Authors: Jenny Hötzel, Nathaniel Melling, Julia Müller, Adam Polonski, Gerrit Wolters-Eisfeld, Jakob R. Izbicki, Karl-F. Karstens, Michael Tachezy

Published in: Journal of Cancer Research and Clinical Oncology | Issue 9/2019

Login to get access

Abstract

Background

The cell adhesion molecule close homologue of L1 (CHL1) is a potential tumour suppressor and was recently detected in non-small cell lung cancer (NSCLC) specimens. The expression pattern, prognostic, and functional role of CHL1 in NSCLCs is unknown.

Methods

We evaluated the protein expression of CHL1 by immunohistochemistry in 2161 NSCLC patients based on a tissue microarray. The results were correlated with clinical, histopathological, and patient survival data (Chi square test, t test, and log-rank test, respectively). A multivariate analysis (Cox regression) was performed to validate its impact on patients’ survival.

Results

CHL1 was expressed in NSCLC patients and was significantly overexpressed in lung adenocarcinomas and squamous cell carcinomas compared to neuroendocrine and large cell carcinomas of the lung (p < 0.001). CHL1 expression was associated with the T stage in adenocarcinomas (p = 0.011) and with metastatic lymph node status and UICC stage in squamous cell carcinomas (p = 0.034 and p = 0.035, respectively). Increased CHL1 expression was associated with improved survival in univariate (p = 0.031) and multivariate analyses (odds ratio 0.797, 95% confidence interval 0.677–0.939, p = 0.007).

Conclusion

The prognostic significance of CHL1 makes it a potential prognostic and therapeutic target and underlines its role as a tumour suppressor. Further validation studies and functional analyses are needed to investigate its potential role in tumourigenesis and dissemination.
Appendix
Available only for authorised users
Literature
go back to reference Conacci-Sorrell ME, Ben-Yedidia T, Shtutman M, Feinstein E, Einat P, Ben-Ze’ev A (2002) Nr-CAM is a target gene of the beta-catenin/LEF-1 pathway in melanoma and colon cancer and its expression enhances motility and confers tumorigenesis. Genes Dev. 16(16):2058–2072CrossRefPubMedPubMedCentral Conacci-Sorrell ME, Ben-Yedidia T, Shtutman M, Feinstein E, Einat P, Ben-Ze’ev A (2002) Nr-CAM is a target gene of the beta-catenin/LEF-1 pathway in melanoma and colon cancer and its expression enhances motility and confers tumorigenesis. Genes Dev. 16(16):2058–2072CrossRefPubMedPubMedCentral
go back to reference Dancau A-M, Simon R, Mirlacher M, Sauter G (2016) Tissue microarrays. Methods Mol Biol Clifton NJ. 1381:53–65CrossRef Dancau A-M, Simon R, Mirlacher M, Sauter G (2016) Tissue microarrays. Methods Mol Biol Clifton NJ. 1381:53–65CrossRef
go back to reference Frints SGM, Marynen P, Hartmann D, Fryns J-P, Steyaert J, Schachner M et al (2003) CALL interrupted in a patient with non-specific mental retardation: gene dosage-dependent alteration of murine brain development and behavior. Hum Mol Genet 12(13):1463–1474CrossRefPubMed Frints SGM, Marynen P, Hartmann D, Fryns J-P, Steyaert J, Schachner M et al (2003) CALL interrupted in a patient with non-specific mental retardation: gene dosage-dependent alteration of murine brain development and behavior. Hum Mol Genet 12(13):1463–1474CrossRefPubMed
go back to reference Górka B, Skubis-Zegadło J, Mikula M, Bardadin K, Paliczka E, Czarnocka B (2007) NrCAM, a neuronal system cell-adhesion molecule, is induced in papillary thyroid carcinomas. Br J Cancer 97(4):531–538CrossRefPubMedPubMedCentral Górka B, Skubis-Zegadło J, Mikula M, Bardadin K, Paliczka E, Czarnocka B (2007) NrCAM, a neuronal system cell-adhesion molecule, is induced in papillary thyroid carcinomas. Br J Cancer 97(4):531–538CrossRefPubMedPubMedCentral
go back to reference He L-H, Ma Q, Shi Y-H, Ge J, Zhao H-M, Li S-F et al (2013) CHL1 is involved in human breast tumorigenesis and progression. Biochem Biophys Res Commun 438(2):433–438CrossRefPubMed He L-H, Ma Q, Shi Y-H, Ge J, Zhao H-M, Li S-F et al (2013) CHL1 is involved in human breast tumorigenesis and progression. Biochem Biophys Res Commun 438(2):433–438CrossRefPubMed
go back to reference Klat J, Mladenka A, Dvorackova J, Bajsova S, Simetka O (2019) L1CAM as a negative prognostic factor in endometrioid endometrial adenocarcinoma FIGO stage IA-IB. Anticancer Res 39(1):421–424CrossRefPubMed Klat J, Mladenka A, Dvorackova J, Bajsova S, Simetka O (2019) L1CAM as a negative prognostic factor in endometrioid endometrial adenocarcinoma FIGO stage IA-IB. Anticancer Res 39(1):421–424CrossRefPubMed
go back to reference Kotani N, Ida Y, Nakano T, Sato I, Kuwahara R, Yamaguchi A et al (2018) Tumor-dependent secretion of close homolog of L1 results in elevation of its circulating level in mouse model for human lung tumor. Biochem Biophys Res Commun. 501(4):982–987CrossRefPubMed Kotani N, Ida Y, Nakano T, Sato I, Kuwahara R, Yamaguchi A et al (2018) Tumor-dependent secretion of close homolog of L1 results in elevation of its circulating level in mouse model for human lung tumor. Biochem Biophys Res Commun. 501(4):982–987CrossRefPubMed
go back to reference Lo Russo G, Imbimbo M, Corrao G, Proto C, Signorelli D, Vitali M et al (2017) Concomitant EML4-ALK rearrangement and EGFR mutation in non-small cell lung cancer patients: a literature review of 100 cases. Oncotarget. 8(35):59889–59900CrossRefPubMedPubMedCentral Lo Russo G, Imbimbo M, Corrao G, Proto C, Signorelli D, Vitali M et al (2017) Concomitant EML4-ALK rearrangement and EGFR mutation in non-small cell lung cancer patients: a literature review of 100 cases. Oncotarget. 8(35):59889–59900CrossRefPubMedPubMedCentral
go back to reference Martín-Sánchez E, Mendaza S, Ulazia-Garmendia A, Monreal-Santesteban I, Blanco-Luquin I, Córdoba A et al (2017) CHL1 hypermethylation as a potential biomarker of poor prognosis in breast cancer. Oncotarget. 8(9):15789–15801CrossRefPubMedPubMedCentral Martín-Sánchez E, Mendaza S, Ulazia-Garmendia A, Monreal-Santesteban I, Blanco-Luquin I, Córdoba A et al (2017) CHL1 hypermethylation as a potential biomarker of poor prognosis in breast cancer. Oncotarget. 8(9):15789–15801CrossRefPubMedPubMedCentral
go back to reference Naus S, Richter M, Wildeboer D, Moss M, Schachner M, Bartsch JW (2004) Ectodomain shedding of the neural recognition molecule CHL1 by the metalloprotease-disintegrin ADAM8 promotes neurite outgrowth and suppresses neuronal cell death. J Biol Chem 279(16):16083–16090CrossRefPubMed Naus S, Richter M, Wildeboer D, Moss M, Schachner M, Bartsch JW (2004) Ectodomain shedding of the neural recognition molecule CHL1 by the metalloprotease-disintegrin ADAM8 promotes neurite outgrowth and suppresses neuronal cell death. J Biol Chem 279(16):16083–16090CrossRefPubMed
go back to reference Ognibene M, Pagnan G, Marimpietri D, Cangelosi D, Cilli M, Benedetti MC et al (2018) CHL1 gene acts as a tumor suppressor in human neuroblastoma. Oncotarget. 9(40):25903–25921CrossRefPubMedPubMedCentral Ognibene M, Pagnan G, Marimpietri D, Cangelosi D, Cilli M, Benedetti MC et al (2018) CHL1 gene acts as a tumor suppressor in human neuroblastoma. Oncotarget. 9(40):25903–25921CrossRefPubMedPubMedCentral
go back to reference Raveh S, Gavert N, Ben-Ze’ev A (2009) L1 cell adhesion molecule (L1CAM) in invasive tumors. Cancer Lett. 282(2):137–145CrossRefPubMed Raveh S, Gavert N, Ben-Ze’ev A (2009) L1 cell adhesion molecule (L1CAM) in invasive tumors. Cancer Lett. 282(2):137–145CrossRefPubMed
go back to reference Reck M, Popat S, Reinmuth N, De Ruysscher D, Kerr KM, Peters S et al (2014) Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol Off J Eur Soc Med Oncol. 25(Suppl 3):iii27–iii39CrossRef Reck M, Popat S, Reinmuth N, De Ruysscher D, Kerr KM, Peters S et al (2014) Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol Off J Eur Soc Med Oncol. 25(Suppl 3):iii27–iii39CrossRef
go back to reference Ross DT, Scherf U, Eisen MB, Perou CM, Rees C, Spellman P et al (2000) Systematic variation in gene expression patterns in human cancer cell lines. Nat Genet 24(3):227–235CrossRefPubMed Ross DT, Scherf U, Eisen MB, Perou CM, Rees C, Spellman P et al (2000) Systematic variation in gene expression patterns in human cancer cell lines. Nat Genet 24(3):227–235CrossRefPubMed
go back to reference Sakurai K, Migita O, Toru M, Arinami T (2002) An association between a missense polymorphism in the close homologue of L1 (CHL1, CALL) gene and schizophrenia. Mol Psychiatry. 7(4):412–415CrossRefPubMed Sakurai K, Migita O, Toru M, Arinami T (2002) An association between a missense polymorphism in the close homologue of L1 (CHL1, CALL) gene and schizophrenia. Mol Psychiatry. 7(4):412–415CrossRefPubMed
go back to reference Senchenko VN, Krasnov GS, Dmitriev AA, Kudryavtseva AV, Anedchenko EA, Braga EA et al (2011) Differential expression of CHL1 gene during development of major human cancers. PLoS One 6(3):e15612CrossRefPubMedPubMedCentral Senchenko VN, Krasnov GS, Dmitriev AA, Kudryavtseva AV, Anedchenko EA, Braga EA et al (2011) Differential expression of CHL1 gene during development of major human cancers. PLoS One 6(3):e15612CrossRefPubMedPubMedCentral
go back to reference Shen M, Ren X (2017) Highlights on immune checkpoint inhibitors in non-small cell lung cancer. Tumour Biol J Int Soc Oncodevelopmental Biol Med. 39(3):1010428317695013CrossRef Shen M, Ren X (2017) Highlights on immune checkpoint inhibitors in non-small cell lung cancer. Tumour Biol J Int Soc Oncodevelopmental Biol Med. 39(3):1010428317695013CrossRef
go back to reference Siesser PF, Maness PF (2009) L1 cell adhesion molecules as regulators of tumor cell invasiveness. Cell Adhes Migr. 3(3):275–277CrossRef Siesser PF, Maness PF (2009) L1 cell adhesion molecules as regulators of tumor cell invasiveness. Cell Adhes Migr. 3(3):275–277CrossRef
go back to reference Simon R, Mirlacher M, Sauter G (2010) Immunohistochemical analysis of tissue microarrays. Methods Mol Biol Clifton NJ. 664:113–126CrossRef Simon R, Mirlacher M, Sauter G (2010) Immunohistochemical analysis of tissue microarrays. Methods Mol Biol Clifton NJ. 664:113–126CrossRef
go back to reference Tachezy M, Zander H, Marx AH, Gebauer F, Rawnaq T, Kaifi JT et al (2011) ALCAM (CD166) expression as novel prognostic biomarker for pancreatic neuroendocrine tumor patients. J Surg Res 170(2):226–232CrossRefPubMed Tachezy M, Zander H, Marx AH, Gebauer F, Rawnaq T, Kaifi JT et al (2011) ALCAM (CD166) expression as novel prognostic biomarker for pancreatic neuroendocrine tumor patients. J Surg Res 170(2):226–232CrossRefPubMed
go back to reference Tang H, Jiang L, Zhu C, Liu R, Wu Y, Yan Q et al (2019) Loss of cell adhesion molecule L1 like promotes tumor growth and metastasis in esophageal squamous cell carcinoma. Oncogene 8:1CrossRef Tang H, Jiang L, Zhu C, Liu R, Wu Y, Yan Q et al (2019) Loss of cell adhesion molecule L1 like promotes tumor growth and metastasis in esophageal squamous cell carcinoma. Oncogene 8:1CrossRef
go back to reference Wei MH, Karavanova I, Ivanov SV, Popescu NC, Keck CL, Pack S et al (1998) In silico-initiated cloning and molecular characterization of a novel human member of the L1 gene family of neural cell adhesion molecules. Hum Genet 103(3):355–364CrossRefPubMed Wei MH, Karavanova I, Ivanov SV, Popescu NC, Keck CL, Pack S et al (1998) In silico-initiated cloning and molecular characterization of a novel human member of the L1 gene family of neural cell adhesion molecules. Hum Genet 103(3):355–364CrossRefPubMed
go back to reference Went P, Vasei M, Bubendorf L, Terracciano L, Tornillo L, Riede U et al (2006) Frequent high-level expression of the immunotherapeutic target Ep-CAM in colon, stomach, prostate and lung cancers. Br J Cancer 94(1):128–135CrossRefPubMedPubMedCentral Went P, Vasei M, Bubendorf L, Terracciano L, Tornillo L, Riede U et al (2006) Frequent high-level expression of the immunotherapeutic target Ep-CAM in colon, stomach, prostate and lung cancers. Br J Cancer 94(1):128–135CrossRefPubMedPubMedCentral
go back to reference Zamay TN, Zamay GS, Kolovskaya OS, Zukov RA, Petrova MM, Gargaun A et al (2017) Current and prospective protein biomarkers of lung cancer. Cancers. 9(11):155CrossRefPubMedCentral Zamay TN, Zamay GS, Kolovskaya OS, Zukov RA, Petrova MM, Gargaun A et al (2017) Current and prospective protein biomarkers of lung cancer. Cancers. 9(11):155CrossRefPubMedCentral
go back to reference Zecchini S, Cavallaro U (2010) Neural cell adhesion molecule in cancer: expression and mechanisms. Adv Exp Med Biol 663:319–333CrossRefPubMed Zecchini S, Cavallaro U (2010) Neural cell adhesion molecule in cancer: expression and mechanisms. Adv Exp Med Biol 663:319–333CrossRefPubMed
Metadata
Title
Protein expression of close homologue of L1 (CHL1) is a marker for overall survival in non-small cell lung cancer (NSCLC)
Authors
Jenny Hötzel
Nathaniel Melling
Julia Müller
Adam Polonski
Gerrit Wolters-Eisfeld
Jakob R. Izbicki
Karl-F. Karstens
Michael Tachezy
Publication date
01-09-2019
Publisher
Springer Berlin Heidelberg
Published in
Journal of Cancer Research and Clinical Oncology / Issue 9/2019
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-019-02989-x

Other articles of this Issue 9/2019

Journal of Cancer Research and Clinical Oncology 9/2019 Go to the issue