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Roles in Cancer Biological Processes and Potential Clinical Value Cancer Biol Med 2020. doi: 10.20892/j.issn.2095-3941.2020.0032 REVIEW CMTM family proteins 1–8: roles in cancer biological processes and potential clinical value Jie Wu*, Lan Li*, Siyi Wu, Bin Xu Cancer Center, Renmin Hospital of Wuhan University, Wuhan 430060, China ABSTRACT The CKLF-like MARVEL transmembrane domain containing (CMTM) family of genes comprises CKLF and CMTM1–8 (previously called chemokine-like factor superfamily 1–8, CKLFSF1–8). The CMTM family proteins contain a structurally conserved MAL and related proteins for vesicle trafficking and membrane linking (MARVEL) domain. Dysregulated expression of multiple CMTM family members is a common feature in many human cancer types. CMTM proteins control critical biological processes in cancer development, including growth factor receptor activation and recycling, cell proliferation, apoptosis, metastasis, and immune evasion. Emerging in vivo and in vitro evidence indicates that the mechanisms of action of most CMTM proteins are complex and multifactorial. This review highlights new findings regarding the roles of CMTM1–8 in cancer, particularly in tumor growth, metastasis, and immune evasion. Additionally, the potential clinical value of CMTMs as novel drug targets or biomarkers is discussed. KEYWORDS CMTM family; cancer; cell cycle; EGFR; EMT; apoptosis; tumor immunity Introduction CMTM genes have been reported to be differentially expressed between tumor and normal tissue, thus suggesting Cancer is a highly heterogeneous group of diseases and one that CMTMs may actively regulate tumor development in of the leading causes of death worldwide. Each tumor type various cancer types4-10. The functions of CMTM family pro- exhibits distinct biological characteristics, clinical features, teins in tumor growth, metastasis, and antitumor immunity outcomes, and responses to therapies. Although the mecha- are well recognized11-14. In addition, CMTM family proteins nisms involved in cancer development have been extensively play crucial roles in mediating the clinical characteristics of studied, much remains to be learned about cancer-associated tumors, including promoting chemotherapeutic resistance in biological regulation. The CKLF-like MARVEL transmem- non-small cell lung cancer (NSCLC)15, and have prognostic brane domain containing (CMTM) family of genes comprises value in multiple cancers15-18. In this review, we focus on the CKLF and CMTM1–8, and their encoded proteins are struc- CMTM family’s biological effects in tumors and potential clin- turally characterized as similar to chemokines and members ical applications. of the transmembrane-4 superfamily (TM4SF). The CMTM family was first cloned and reported in 20011. To date, CMTM Structural characteristics of CMTM family members have been revealed to function as regulators family gene transcripts and proteins in various diseases, including autoimmune2 and cardiovascu- lar diseases3. Moreover, recent in-depth studies have indicated CMTM1–8 were first identified in 2003 through analysis com- that CMTMs also play crucial roles in cancer-associated bio- bining CKLF2 cDNA and protein sequence analysis with exper- logical regulation. imental validation19. CMTM1 contains a C-c motif and exhib- its higher sequence identity with chemokines than do other *These authors contributed equally to this work. Correspondence to: Bin Xu CMTMs. CMTM8 has the lowest sequence identity with chemok- 19 E-mail: [email protected] ines but has 39.3% amino acid similarity with TM4SF11 , and ORCID ID: https://orcid.org/0000-0002-0499-0430 the level of sequence identity between CMTM2–7 and chemok- Received January 30, 2020; accepted June 8, 2020. ines is intermediate between those of CMTM1 and CMTM819. Available at www.cancerbiomed.org ©2020 Cancer Biology & Medicine. Creative Commons Thus, proteins encoded by CMTM1–8 have a common feature Attribution-NonCommercial 4.0 International License of structural similarity with classical chemokines and TM4SF. Cancer Biol Med Vol 17, No 3 August 2020 529 Most CMTM transcripts have multiple alternative splicing of individual CMTM family members in biological processes forms, but all the resulting protein products contain a MAL and may depend on the specific alternative splicing isoforms of each related proteins for vesicle trafficking and membrane linking transcript21,22,23. The genes in the CMTM family form 2 gene (MARVEL) domain19. Therefore, these proteins were renamed clusters. The CMTM1–4 genes form a gene cluster on chromo- CMTM1–8, or CKLF-like MARVEL transmembrane domain some 16, whereas CMTM6–8 form the second gene cluster on containing 1–8, whereas they were previously called chemok- chromosome 3p22.3 (Table 1, Figure 1), where many critical ine-like factor superfamily 1–8 (CKLFSF1–8)20. The functions tumor suppressor genes are located. Table 1 Characteristics of CMTM family members Gene Location Main subcellular locations Gene ontology (GO) - biological process CMTM1 16q21 Plasma membrane, extracellular space, Chemotaxis, regulation of signaling receptor activity nucleus, peroxisome CMTM2 16q21 Nucleus, plasma membrane, extracellular Chemotaxis, regulation of signaling receptor activity space, Golgi apparatus, peroxisome, cytosol CMTM3 16q22.1 Plasma membrane, extracellular space, Chemotaxis, regulation of signaling receptor activity, positive regulation of nucleus, endosome B cell receptor signaling pathway CMTM4 16q22.1 Plasma membrane, extracellular space, Chemotaxis, regulation of signaling receptor activity nucleus, Golgi apparatus CMTM5 14q11.2 Plasma membrane, extracellular space Chemotaxis, regulation of signaling receptor activity, negative regulation of myoblast differentiation CMTM6 3p22.3 Plasma membrane, extracellular space, Chemotaxis, regulation of signaling receptor activity, neutrophil degranulation lysosome, cytoskeleton, cytosol, endosome CMTM7 3p22.3 Plasma membrane, extracellular space B-1a B cell differentiation, chemotaxis, regulation of signaling receptor activity CMTM8 3p22.3 Nucleus, plasma membrane and Membrane raft polarization, chemotaxis, protein localization, regulation of extracellular space signaling receptor activity, myelination The information is available in the Gene Cards database: https://www.genecards.org/. Chromosome 16 Chromosome 14 971 bp 167 bp 161 bp 175 bp 90 bp 176 bp 3357 bp 971 bp 353 bp 2602 bp CMTM1 819 bp 153 bp 201 bp 93 bp 85 bp 299 bp CMTM5 123 4 5 6 311 bp 246 bp 222 bp 156 bp 96 bp 121 bp 1284 bp 12 3 4 5 6 CMTM2 CMTM5-v1 124 5 6 15.75 kb CMTM3-v1 123 4 5 6 CMTM5-v2 1 2 3 4 5 6 CMTM3 Chromosome 3 870 bp CMTM8 1.2 kb 12.9 kb 59.7 kb CMTM4 1.2 kb 12.9 kb 59.7 kb 21.35 kb 147 bp 174 bp 117 bp 84 bp 7473 bp 99 bp 177 bp 368 bp 1 2 3 4 4C 4B 4A 3 2 1 CMTM7 26.47 kb CMTM4-v1 4C 4A 3 2 1 CMTM8-v1 1 2 3 4 CMTM8-v2 1 3 4 CMTM4-v2 4C 4B 4A 32 1 CMTM6 : Exon : Intron Figure 1 Chromosome locations and genomic structures of the human CMTMs (modified from references 9, 19, 20, 24, and 25). The sche- matic maps and major splice forms of human CMTM3–CMTM5 and CMTM8 are presented. 530 Wu et al. CMTM family proteins 1–8 in cancer Expression of CMTM family in normal adult and fetal tissues but show decreased expres- members sion with frequent DNA methylation in the promoter regions in most carcinoma cell lines9,29. CMTM6 has been shown to be upregulated in the tissues of some tumors, including gli- The CMTM1–CMTM4 genes are highly expressed in the male omas17,12,30. The pan-cancer expression of CMTM family reproductive system (testis) and compartments in the immune genes and their prognostic value in The Cancer Genome Atlas system, including the bone marrow and peripheral blood cells, (TCGA) database are summarized in Figure 2. such as resting CD19+ cells and activated peripheral blood Many biological processes and molecules, such as DNA monocytes20,26,27. The CMTM3 and CMTM5 genes, as well methylation and microRNAs (Figure 3A), regulate the as the CMTM7 and CMTM8 genes18,28, are broadly expressed expression of CMTM family members. The CMTM3 gene 1 2 3 4 5 6 7 8 A CMTM 1CMTM 2 CMTM 3CMTM 4 CMTM 5 CMTM 6CMTM 7 CMTM 8 B CMTM CMTM CMTM CMTM CMTM CMTM CMTM CMTM l l ACC (n = 79) P ≥ 0.05 BLCA (n = 408) BRCA (n = 1100) Normal Normal Norma Normal Normal Norma Normal Normal Tumor Tumor Tumor Tumor Tumor Tumor Tumor Tumor P < 0.05 BRCA−Basal (n = 191) BLCA 6 BRCA−Her2 (n = 82) BRCA−LumA (n = 568) Z-score BRCA BRCA−LumB (n = 219) 7.2 CESC 5 CESC (n = 306) CHOL (n = 36) CHOL 4 COAD (n = 458) COAD DLBC (n = 48) ESCA (n = 185) ESCA GBM (n = 153) 0.0 3 HNSC (n = 522) HNSC HNSC−HPV− (n = 422) KICH HNSC−HPV+ (n = 98) 2 KICH (n = 66) −6.1 KIRC KIRC (n = 533) KIRP (n = 290) s 1 KIRP LAML (n = 173) LIHC LGG (n = 516) 0 LIHC (n = 371) LUAD LUAD (n = 515) LUSC (n = 501) LUSC MESO (n = 87) Cancer type PAAD OV (n = 303) PAAD (n = 179) PCPG PCPG (n = 181) PRAD PRAD (n = 498) READ (n = 166) READ SARC (n = 260) SKCM (n = 471) SARC SKCM−Metastasis (n = 368) SKCM SKCM−Primary (n = 103) STAD (n = 415) STAD TGCT (n = 150) THCA (n = 509) THCA THYM (n = 120) THYM UCEC (n = 545) UCS (n = 57) UCEC UVM (n = 80) Log (TPM + 1) Figure 2 Pan-cancer expression of CMTMs and their prognostic value in TCGA. (A) Expression matrix plots showing gene expression of CMTMs in different cancers. The results were derived from the Gene Expression Profiling Interactive Analysis (GEPIA) database. The density of the color in each block represents the median expression value of a gene in a given tissue, normalized by the maximum median expression value across all blocks. (B) The prognostic value of CMTM gene expression. The results were derived from the Tumor Immune Estimation Resource (TIMER) database. The univariate Cox proportional hazard model was used to evaluate the significance of gene expression outcomes (the gene expression was treated as continuous variable).
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