Bioinformatics-Based Discovery of CKLF-Like MARVEL Transmembrane Member 5 as a Novel Biomarker for Breast Cancer

Chemokine-like factor (CKLF)-like MARVEL transmembrane members (CMTMs) represent a novel protein family linking the chemokine and transmembrane-4 superfamily families, which potentially play several roles in diverse physiological and pathological processes. The detailed functions and underlying molecular mechanisms of CMTMs remain elusive in breast cancer. Herein, we performed a comprehensive bioinformatic analysis to investigate the prognostic effect, potential functions, and biomolecular regulatory network of CMTMs in breast cancer. The mRNA expression level of CMTM5, in particular, was significantly downregulated in breast cancer; moreover, high mRNA expression level of CMTM5 was significantly associated with better relapse-free survival. DNA promoter hypermethylation of CMTM5 was negatively correlated with its mRNA expression levels. Furthermore, CMTM5 strongly associated with pathway in MARVEL domains, chemotaxis, cytokines, transmembrane structures, and integral component of membrane. For example, genes related to MARVEL domains, transmembrane structures, and chemokines were significantly enriched. Our findings indicate that CMTM5 can be used as a prognostic biomarker and potential therapeutic target for breast cancer.

[1]  Xiaoman Li,et al.  Research Advances in CKLF-like MARVEL Transmembrane Domain-containing Family in Non-small Cell Lung Cancer , 2019, International journal of biological sciences.

[2]  Yili Yang,et al.  Overexpression of CMTM7 inhibits cell growth and migration in liver cancer , 2019, The Kaohsiung journal of medical sciences.

[3]  P. Fasching,et al.  Primary Therapy of Early Breast Cancer: Evidence, Controversies, Consensus , 2019, Geburtshilfe und Frauenheilkunde.

[4]  R. Lara-Lemus.  On The Role of Myelin and Lymphocyte Protein (MAL) In Cancer: A Puzzle With Two Faces , 2019, Journal of Cancer.

[5]  S. Hochwald,et al.  Expression of tetraspanins NET-6 and CD151 in breast cancer as a potential tumor biomarker , 2019, Clinical and Experimental Medicine.

[6]  J. Kong,et al.  Expression and Clinical Significance of CMTM6 in Hepatocellular Carcinoma. , 2019, DNA and cell biology.

[7]  Andrew J. Oler,et al.  Co-Expression of VEGF and IL-6 Family Cytokines is Associated with Decreased Survival in HER2 Negative Breast Cancer Patients: Subtype-Specific IL-6 Family Cytokine-Mediated VEGF Secretion12 , 2018, Translational oncology.

[8]  Shuo Li,et al.  Up‐regulation of miR‐10b‐3p promotes the progression of hepatocellular carcinoma cells via targeting CMTM5 , 2018, Journal of cellular and molecular medicine.

[9]  H. Woo,et al.  Identification of genomic aberrations associated with lymph node metastasis in diffuse-type gastric cancer , 2018, Experimental & Molecular Medicine.

[10]  G. Turashvili,et al.  Tumor Heterogeneity in Breast Cancer , 2017, Front. Med..

[11]  Shengkui Tan,et al.  Clinical significance of CMTM4 expression in hepatocellular carcinoma , 2017, OncoTargets and therapy.

[12]  L. H. Mendoza,et al.  El cáncer de mama en el siglo XXI: de la detección precoz a los nuevos tratamientos , 2017 .

[13]  J. Bonilla,et al.  Breast cancer in the 21st century: From early detection to new therapies , 2017 .

[14]  S. Dawson,et al.  CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity , 2017, Nature.

[15]  Chad J. Creighton,et al.  UALCAN: A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses , 2017, Neoplasia.

[16]  H. Horlings,et al.  Identification of CMTM6 and CMTM4 as PD-L1 protein regulators , 2017, Nature.

[17]  Shao-bin Zheng,et al.  CMTM5 inhibits renal cancer cell growth through inducing cell-cycle arrest and apoptosis , 2017, Oncology letters.

[18]  A. Lánczky,et al.  miRpower: a web-tool to validate survival-associated miRNAs utilizing expression data from 2178 breast cancer patients , 2016, Breast Cancer Research and Treatment.

[19]  B. Pang,et al.  Cancer Research Advance in CKLF-like MARVEL Transmembrane Domain Containing Member Family (Review). , 2016, Asian Pacific journal of cancer prevention : APJCP.

[20]  Kexin Xu,et al.  Functional characterization of the tumor suppressor CMTM8 and its association with prognosis in bladder cancer , 2016, Tumor Biology.

[21]  Shailesh Singh,et al.  CXCR6-CXCL16 axis promotes prostate cancer by mediating cytoskeleton rearrangement via Ezrin activation and αvβ3 integrin clustering , 2016, Oncotarget.

[22]  Qi-hua He,et al.  CMTM7 knockdown increases tumorigenicity of human non-small cell lung cancer cells and EGFR-AKT signaling by reducing Rab5 activation , 2015, Oncotarget.

[23]  Tao Xu,et al.  CMTM4 is frequently downregulated and functions as a tumour suppressor in clear cell renal cell carcinoma , 2015, Journal of experimental & clinical cancer research : CR.

[24]  Weidong Yu,et al.  CMTM8 inhibits the carcinogenesis and progression of bladder cancer , 2015, Oncology reports.

[25]  A. Koch,et al.  MEXPRESS: visualizing expression, DNA methylation and clinical TCGA data , 2015, BMC Genomics.

[26]  A. Bosserhoff,et al.  Systematic investigation of CMTM family genes suggests relevance to glioblastoma pathogenesis and CMTM1 and CMTM3 as priority targets , 2015, Genes, chromosomes & cancer.

[27]  X. Wang,et al.  CMTM5 is reduced in prostate cancer and inhibits cancer cell growth in vitro and in vivo , 2015, Clinical and Translational Oncology.

[28]  C. Mathers,et al.  Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012 , 2015, International journal of cancer.

[29]  Hsien-Da Huang,et al.  MethHC: a database of DNA methylation and gene expression in human cancer , 2014, Nucleic Acids Res..

[30]  Davide Heller,et al.  STRING v10: protein–protein interaction networks, integrated over the tree of life , 2014, Nucleic Acids Res..

[31]  J. Morales-Montor,et al.  The Role of Chemokines in Breast Cancer Pathology and Its Possible Use as Therapeutic Targets , 2014, Journal of immunology research.

[32]  Heyu Zhang,et al.  CMTM5 exhibits tumor suppressor activity through promoter methylation in oral squamous cell carcinoma. , 2014, Biochemical and biophysical research communications.

[33]  H. Kalofonos,et al.  Expression of claudins-1, -4, -5, -7 and occludin in hepatocellular carcinoma and their relation with classic clinicopathological features and patients' survival. , 2014, In vivo.

[34]  J. Xie,et al.  CMTM3 is frequently reduced in clear cell renal cell carcinoma and exhibits tumor suppressor activities , 2014, Clinical and Translational Oncology.

[35]  Jun Wang,et al.  Change of CMTM7 expression, a potential tumor suppressor, is associated with poor clinical outcome in human non‐small cell lung cancer , 2013, Chinese medical journal.

[36]  D. Taub,et al.  Differential G protein subunit expression by prostate cancer cells and their interaction with CXCR5 , 2013, Molecular Cancer.

[37]  Benjamin E. Gross,et al.  The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. , 2012, Cancer discovery.

[38]  Robin L. Anderson,et al.  Oncostatin m promotes mammary tumor metastasis to bone and osteolytic bone degradation. , 2012, Genes & cancer.

[39]  Stephanie Alexander,et al.  Cancer Invasion and the Microenvironment: Plasticity and Reciprocity , 2011, Cell.

[40]  John S. Condeelis,et al.  Chemotaxis in cancer , 2011, Nature Reviews Cancer.

[41]  Shailesh Singh,et al.  Chemokines: key players in cancer progression and metastasis. , 2011, Frontiers in bioscience.

[42]  B. Kong,et al.  Reduced CMTM5 Expression Correlates With Carcinogenesis in Human Epithelial Ovarian Cancer , 2011, International Journal of Gynecologic Cancer.

[43]  J. Scheller,et al.  The pro- and anti-inflammatory properties of the cytokine interleukin-6. , 2011, Biochimica et biophysica acta.

[44]  G. Getz,et al.  GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers , 2011, Genome Biology.

[45]  Antoine M. van Oijen,et al.  Real-time single-molecule observation of rolling-circle DNA replication , 2009, Nucleic acids research.

[46]  Brad T. Sherman,et al.  Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists , 2008, Nucleic acids research.

[47]  Jun Wang,et al.  Expression of CKLF1,CMTM1,CMTM2 and CMTM4 in non-small cell lung cancer , 2008 .

[48]  Q. Tao,et al.  CMTM5 Exhibits Tumor Suppressor Activities and Is Frequently Silenced by Methylation in Carcinoma Cell Lines , 2007, Clinical Cancer Research.

[49]  J. Condeelis,et al.  Regulation of the actin cytoskeleton in cancer cell migration and invasion. , 2007, Biochimica et biophysica acta.

[50]  Jae Hoon Kim,et al.  Analysis of chromosomal changes in serous ovarian carcinoma using high‐resolution array comparative genomic hybridization: Potential predictive markers of chemoresistant disease , 2007, Genes, chromosomes & cancer.

[51]  J. Scheller,et al.  Updating interleukin-6 classic- and trans-signaling , 2006 .

[52]  Francis Lin,et al.  Differential effects of EGF gradient profiles on MDA-MB-231 breast cancer cell chemotaxis. , 2004, Experimental cell research.

[53]  C. Jorcyk,et al.  Oncostatin M induces cell detachment and enhances the metastatic capacity of T-47D human breast carcinoma cells. , 2004, Cytokine.

[54]  Yingyu Chen,et al.  Identification of eight genes encoding chemokine-like factor superfamily members 1-8 (CKLFSF1-8) by in silico cloning and experimental validation. , 2003, Genomics.

[55]  A. Ben-Baruch,et al.  Host microenvironment in breast cancer development: Inflammatory cells, cytokines and chemokines in breast cancer progression: reciprocal tumor–microenvironment interactions , 2002, Breast Cancer Research.

[56]  L. Ellis,et al.  Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis , 2002, Oncogene.

[57]  Shengkui Tan,et al.  Clinical significance of CMTM 4 expression in hepatocellular carcinoma , 2017 .

[58]  J. Merino Bonilla,et al.  Breast cancer in the 21st century: from early detection to new therapies. , 2017, Radiologia.

[59]  B. Pang,et al.  Advances Regarding the CKLF-like MARVEL Transmembrane Domain Containing Family , 2016 .

[60]  W. Coleman,et al.  Enhancement of chemotherapeutic efficacy in hypermethylator breast cancer cells through targeted and pharmacologic inhibition of DNMT3b , 2011, Breast Cancer Research and Treatment.

[61]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[62]  T. Barrette,et al.  ONCOMINE: a cancer microarray database and integrated data-mining platform. , 2004, Neoplasia.