Top

Journal of Cancer Research and Clinical Oncology

Published in:

01-10-2020 | Metastasis | Original Article – Cancer Research

A novel metastatic promoter CEMIP and its downstream molecular targets and signaling pathway of cellular migration and invasion in SCLC cells based on proteome analysis

Authors: Li Li, Yingxing Pan, Xiaoxiang Mo, Tongtong Wei, Jinjing Song, Min Luo, Guolin Huang, Cuifang Teng, Kai Liang, Naiquan Mao, Jie Yang

Published in: Journal of Cancer Research and Clinical Oncology | Issue 10/2020

Abstract

Purpose

Metastasis is an unavoidable event happened among almost all small cell lung cancer (SCLC) patients. However, the molecular driven factors have not been elucidated. Recently, a novel hydrolase called cell migration inducing hyaluronidase (CEMIP) triggered both migration and invasion in many tumors but not SCLC. Therefore, in this study, we verified that CEMIP promoted migration and invasion in SCLC and applied proteomics analysis to screen out potential target profiles and the signaling pathway related to CEMIP regulation.

Method

Immunofluorescence was conducted to exam the expression of CEMIP on SCLC and paired adjacent normal tissues among enrollment. RT-qPCR and Western blot (WB) assays were conducted to valuate cellular protein and mRNA expression of CEMIP and EMT markers. Lentivirus-CEMIP-shRNAs and CEMIP plasmid were used for expression manipulating. Changes of cellular migration and invasion were tested through transwell assays. Tandem Mass Tag (TMT) peptide labeling coupled with LC–MS/MS was used for quantifying proteins affected by reducing expression of CEMIP on H446 cells.

Results

The expression of CEMIP showed 1.64 ± 0.16-fold higher in SCLC tissues than their normal counterpart. Decreasing the expression of CEMIP on SCLC cells H446 regressed both cellular migration and invasion ability, whereas the promoting cellular migration and invasion was investigated through over-expressing CEMIP on H1688. Proteomic and bioinformatics analysis revealed that total 215 differentially expressed proteins (DEPs) that either their increasing or decreasing relative expression met threshold of 1.2-fold changes with p value ≤ 0.05. The dramatic up-regulated DEPs included an unidentified peptide sequence (encoded by cDNA FLJ52096) SPICE1 and CRYAB, while the expression of S100A6 was largely down-regulated. DEPs mainly enriched on caveolae of cellular component, calcium ion binding of biological process and epithelial cell migration of molecular function. KEGG enrichment indicated that DEPs mainly exerted their function on TGF-β, GABAergic synapse and MAPK signaling pathway.

Conclusion

It is the first report illustrating that CEMIP might be one of the metastatic triggers in SCLC. And also, it provided possible molecular mechanism cue and potential downstream target on CEMIP-induced cellular migration and invasion on SCLC.

Available only for authorised users

Al-Ismaeel Q, Neal CP, Al-Mahmoodi H, Almutairi Z, Al-Shamarti I, Straatman K, Jaunbocus N, Irvine A, Issa E, Moreman C et al (2019) ZEB1 and IL-6/11-STAT3 signalling cooperate to define invasive potential of pancreatic cancer cells via differential regulation of the expression of S100 proteins. Br J Cancer 121(1):65–75PubMedPubMedCentral

Amarasena IU, Chatterjee S, Walters JA, Wood-Baker R, Fong KM (2015) Platinum versus non-platinum chemotherapy regimens for small cell lung cancer. Cochrane Database Syst Rev 8:CD006849

Birkenkamp-Demtroder K, Maghnouj A, Mansilla F, Thorsen K, Andersen CL, Oster B, Hahn S, Orntoft TF (2011) Repression of KIAA1199 attenuates Wnt-signalling and decreases the proliferation of colon cancer cells. Br J Cancer 105(4):552–561PubMedPubMedCentral

Calvo FQ, Fillet M, de Seny D, Meuwis MA, Maree R, Crahay C, Paulissen G, Rocks N, Gueders M, Wehenkel L et al (2009) Biomarker discovery in asthma-related inflammation and remodeling. Proteomics 9(8):2163–2170PubMed

Chen L, Shi K, Andersen TL, Qiu W, Kassem M (2019) KIAA1199 is a secreted molecule that enhances osteoblastic stem cell migration and recruitment. Cell Death Dis 10(2):126PubMedPubMedCentral

Chen W, Zheng R, Zhang S, Zeng H, Zuo T, Xia C, Yang Z, He J (2017) Cancer incidence and mortality in China in 2013: an analysis based on urbanization level. Chin J Cancer Res 29(1):1–10PubMedPubMedCentral

Duan L, Wu R, Zou Z, Wang H, Ye L, Li H, Yuan S, Li X, Zha H, Sun H et al (2014) S100A6 stimulates proliferation and migration of colorectal carcinoma cells through activation of the MAPK pathways. Int J Oncol 44(3):781–790PubMed

Duong HQ, Nemazanyy I, Rambow F, Tang SC, Delaunay S, Tharun L, Florin A, Buttner R, Vandaele D, Close P (2018) The endosomal protein CEMIP links WNT signaling to MEK1-ERK1/2 activation in selumetinib-resistant intestinal organoids. Cancer Res 78(16):4533–4548PubMed

Fink SP, Myeroff LL, Kariv R, Platzer P, Xin B, Mikkola D, Lawrence E, Morris N, Nosrati A, Willson JK et al (2015) Induction of KIAA1199/CEMIP is associated with colon cancer phenotype and poor patient survival. Oncotarget 6(31):30500–30515PubMedPubMedCentral

Gazdar AF, Bunn PA, Minna JD (2017) Small-cell lung cancer: what we know, what we need to know and the path forward. Nat Rev Cancer 17(12):725–737PubMed

Hoftberger R, Titulaer MJ, Sabater L, Dome B, Rozsas A, Hegedus B, Hoda MA, Laszlo AHJ, Harms L et al (2013) Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients. Neurology 81(17):1500–1506PubMedPubMedCentral

Huntley SP, Davies M, Matthews JB, Thomas G, Marshall J, Robinson CM, Eveson JW, Paterson IC, Prime SS (2004) Attenuated type II TGF-beta receptor signalling in human malignant oral keratinocytes induces a less differentiated and more aggressive phenotype that is associated with metastatic dissemination. Int J Cancer 110(2):170–176PubMed

Izzi L, Attisano L (2004) Regulation of the TGFbeta signalling pathway by ubiquitin-mediated degradation. Oncogene 23(11):2071–2078PubMed

Jakowlew SB (2006) Transforming growth factor-beta in cancer and metastasis. Cancer Metastasis Rev 25(3):435–457PubMed

Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 6(2):69–90

Jin C, Yang YA, Anver MR, Morris N, Wang X, Zhang YE (2009) Smad ubiquitination regulatory factor 2 promotes metastasis of breast cancer cells by enhancing migration and invasiveness. Cancer Res 69(3):735–740PubMedPubMedCentral

Kikuchi M, Yamashita K, Waraya M, Minatani N, Ushiku H, Kojo K, Ema A, Kosaka Y, Katoh H, Sengoku N et al (2016) Epigenetic regulation of ZEB1-RAB25/ESRP1 axis plays a critical role in phenylbutyrate treatment-resistant breast cancer. Oncotarget 7(2):1741–1753PubMed

Koga A, Sato N, Kohi S, Yabuki K, Cheng XB, Hisaoka M, Hirata K (2017) KIAA1199/CEMIP/HYBID overexpression predicts poor prognosis in pancreatic ductal adenocarcinoma. Pancreatology 17(11):115–122PubMed

Kohi S, Sato N, Koga A, Matayoshi N, Hirata K (2017) KIAA1199 is induced by inflammation and enhances malignant phenotype in pancreatic cancer. Oncotarget 8(10):17156–17163PubMedPubMedCentral

Li A, Shi D, Xu B, Wang J, Tang YL, Xiao W, Shen G, Deng W, Zhao C (2017a) S100A6 promotes cell proliferation in human nasopharyngeal carcinoma via the p38/MAPK signaling pathway. Mol Carcinog 56(3):972–984PubMed

Li C, Zhang F, Wang Y (2010) S100A proteins in the pathogenesis of experimental corneal neovascularization. Mol Vis 16:2225–2235PubMedPubMedCentral

Li H, Zhang Z, Chen L, Sun X, Zhao Y, Guo Q, Zhu S, Li P, Min L, Zhang S (2019) Cytoplasmic Asporin promotes cell migration by regulating TGF-beta/Smad2/3 pathway and indicates a poor prognosis in colorectal cancer. Cell Death Dis 10(2):109PubMedPubMedCentral

Li L, Yan LH, Manoj S, Li Y, Lu L (2017b) Central role of CEMIP in tumorigenesis and its potential as therapeutic target. J Cancer 8(12):2238–2246PubMedPubMedCentral

Oneyama M, Sakamoto N, Oue N, Kimura Y, Hiroshima Y, Hashimoto I, Hara K, Maezawa Y, Kano K, Aoyama T et al (2019) Clinical significance of KIAA1199 as a novel target for gastric cancer drug therapy. Anticancer Res 39(12):6567–6573PubMed

Parkin A, Man J, Timpson P, Pajic M (2019) Targeting the complexity of Src signalling in the tumour microenvironment of pancreatic cancer: from mechanism to therapy. FBES J 286(18):3510–3539

Peifer M, Fernandez-Cuesta L, Sos ML, George J, Seidel D, Kasper LH, Plenker D, Leenders F, Sun R, Zander T et al (2012) Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 44(10):1104–1110PubMedPubMedCentral

Peng Y, Lin J, Ma J, Lin K, Xu K, Lin J (2018) Upregulation of S100A6 in patients with endometriosis and its role in ectopic endometrial stromal cells. Gynecol Endocrinol 34(9):815–820PubMed

Powell HA, Tata LJ, Baldwin DR, Potter VA, Stanley RA, Khakwani A, Hubbard RB (2014) Treatment decisions and survival for people with small-cell lung cancer. Br J Cancer 110(4):908–915PubMedPubMedCentral

Rizzolio S, Battistini C, Cagnoni G, Apicella M, Vella V, Giordano S, Tamagnone L (2018) Downregulating neuropilin-2 triggers a novel mechanism enabling EGFR-dependent resistance to oncogene-targeted therapies. Cancer Res 78(4):1058–1068PubMed

Rodrigues G, Hoshino A, Kenific CM, Matei IR, Steiner L, Freitas D (2019) Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis. Nat Cell Biol 21(11):1403–1412PubMedPubMedCentral

Rozycka A, Liguz-Lecznar M (2017) The space where aging acts: focus on the GABAergic synapse. Aging Cell 16(4):634–643PubMedPubMedCentral

Semenova EA, Nagel R, Berns A (2015) Origins, genetic landscape, and emerging therapies of small cell lung cancer. Genes Dev 29(14):1447–1462PubMedPubMedCentral

Shostak K, Zhang X, Hubert P, Goktuna SI, Jiang Z, Klevernic I, Hildebrand J, Roncarati P, Hennuy B, Ladang A et al (2014) NF-kappaB-induced KIAA1199 promotes survival through EGFR signalling. Nat Commun 5:5232PubMedPubMedCentral

Siegel RL, Miller KD (2020) Cancer statistics, 2020. CA Cancer J Clin 70(1):7–30PubMed

Soroosh A, Albeiroti S, West GA, Willard B, Fiocchi C, de la Motte CA (2016) Crohn's disease fibroblasts overproduce the novel protein KIAA1199 to create proinflammatory hyaluronan fragments. Cell Mol Gastroenterol Hepatol 2(3):358–368.e354PubMedPubMedCentral

Suh HN, Jun S, Oh AY, Srivastava M, Lee S, Taniguchi CM, Zhang S, Lee WS, Chen J, Park BJ et al (2016) Identification of KIAA1199 as a biomarker for pancreatic intraepithelial neoplasia. Sci Rep 6:38273PubMedPubMedCentral

Sun JF, Hu JY, Wang GJ, Yang Z, Zhao CL, Zhang XF, Wang JX (2018) LncRNA TUG1 promoted KIAA1199 expression via miR-600 to accelerate cell metastasis and epithelial-mesenchymal transition in colorectal cancer. J Exp Clin Cancer Res 37(1):106PubMedPubMedCentral

Tang Z, Ding Y, Shen Q, Zhang C, Li J, Nazar M, Wang Y, Zhou X, Huang J (2019) KIAA1199 promotes invasion and migration in non-small-cell lung cancer (NSCLC) via PI3K-Akt mediated EMT. J Mol Med (Berl) 97(1):127–140

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65(2015):87–108PubMed

van Meerbeeck JP, Fennell DA, De Ruysscher DK (2011) Small-cell lung cancer. Lancet 378:1741–1755PubMed

Wagner EF, Nebreda AR (2009) Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer 9(8):537–549PubMed

Wang L, Yu T, Li W, Li M, Zuo Q, Zou Q, Xiao B (2019) The miR-29c-KIAA1199 axis regulates gastric cancer migration by binding with WBP11 and PTP4A3. Oncogene 38(17):334–3150

Wisniewski JR, Zougman A, Nagaraj N, Mann M (2009) Universal sample preparation method for proteome analysis. Nat Methods 6(5):359–362PubMed

Wu B, Guo B, Kang J, Deng X, Fan Y, Zhang X, Ai K (2016) Downregulation of Smurf2 ubiquitin ligase in pancreatic cancer cells reversed TGF-beta-induced tumor formation. Tumour Biol. https://doi.org/10.1007/s13277-016-5432-0CrossRefPubMedPubMedCentral

Xu Y, Xu H, Li M, Wu H, Guo Y, Chen J, Shan J, Chen X, Shen J, Ma Q et al (2019) KIAA1199 promotes sorafenib tolerance and the metastasis of hepatocellular carcinoma by activating the EGF/EGFR-dependent epithelial-mesenchymal transition program. Cancer Lett 454:78–89PubMed

Zhao L, Zhang D, Shen Q, Jin M, Lin Z, Ma H, Huang S, Zhou P, Wu G, Zhang T (2019) KIAA1199 promotes metastasis of colorectal cancer cells via microtubule destabilization regulated by a PP2A/stathmin pathway. Oncogene 38(7):935–949PubMed

Title: A novel metastatic promoter CEMIP and its downstream molecular targets and signaling pathway of cellular migration and invasion in SCLC cells based on proteome analysis
Authors: Li Li
Yingxing Pan
Xiaoxiang Mo
Tongtong Wei
Jinjing Song
Min Luo
Guolin Huang
Cuifang Teng
Kai Liang
Naiquan Mao
Jie Yang
Publication date: 01-10-2020
Publisher: Springer Berlin Heidelberg
Keywords: Metastasis
SCLC
SCLC
Published in: Journal of Cancer Research and Clinical Oncology / Issue 10/2020
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-020-03308-5

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Method

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 10/2020

Appropriate arrangement of cancer treatment after COVID-19 epidemic peaks in China

Analyses of expressions and prognostic values of Polo-like kinases in non-small cell lung cancer

Oral cancer awareness campaign in Northern Germany: first positive trends in incidence and tumour stages

Correlations between circulating tumor cell phenotyping and 18F-fluorodeoxyglucose positron emission tomography uptake in non-small cell lung cancer

PD-L1 and IDO1 expression and tumor-infiltrating lymphocytes in osteosarcoma patients: comparative study of primary and metastatic lesions

Systematic review and network meta-analyses of third-line treatments for metastatic colorectal cancer

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials