摘要
Chemokine-like factor-like MARVEL transmembrane domain containing member/chemokine-like factor superfamily member (CMTM/CKLFSF) including CKLF and CMTM1-CMTM8 are a new family of proteins linking chemokines and transmembrane superfamilies. CMTM not only have broad chemotactic activities, but also associate with hematopoietic system, immune system, and tumor development and metastasis closely. CMTM proteins are involved in key biological processes of cancer development, which include activation and recycling of growth factor receptors, cell proliferation and metastasis, and regulation of the tumor immune microenvironment. This is a new focus of research on the relationship between CMTM and tumors, because CMTM4/CMTM6 can be considered as a regulator for programmed cell death ligand 1 (PD-L1). This paper reviews the role of CMTM family members on cancer, especially in tumor growth, metastasis and immune escape, summarize the latest findings on the relationship between CMTM and non-small cell lung cancer, and explores the potential clinical value of CMTM as a novel drug target or biomarker. .
Subject(s)
Humans , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms , MARVEL Domain-Containing Proteins/metabolism , Cell Proliferation , Chemokines/metabolism , Tumor Microenvironment摘要
OBJECTIVE@#To elucidate the correlation between CKLF-like marvel transmembrane domain containing member (CMTM5) gene and the risk of in-stent restenosis (ISR) with coronary artery disease (CAD) patients and to detect the effects and mechanisms of CMTM5-stimulated genes on human vascular endothelial cells (ECs) proliferation and migration.@*METHODS@#A total of 124 hospitalized patients in Shijitan Hospital were enrolled in this study. All the CAD patients were detected with platelet reactivity and grouped into two groups according to platelet reactivity; ISR was conformed by coronary angiography; RT-PCR method was used to detect CMTM5 gene expression; The CMTM5 over expression, reduction and control EC lines were established; Cell count, MTT, Brdu and flow cytometry methods were used to detect the proliferation of ECs, scratch and transwell experiments to test the migration of ECs, Western blot was used to detect signal path expressions.@*RESULTS@#CMTM5 gene expression in HAPR (High on aspirin platelet reactivity) group was 1.72 times compared with No-HAPR group, which was significantly higher than No-HAPR group. HAPR group ISR rate was 25.8% (8 cases), the incidence of No-HAPR ISR group was 9.7% (9 cases), and the results showed that in HAPR group, the incidence of ISR was significantly higher than that in No-HAPR group (P=0.04, OR=0.04, 95%CI=1.16－7.52), which showed that CMTM5 gene was significantly correlated with the risk of ISR. In HAPR group ISR rate was 25.8% (8 cases), the incidence of ISR in No-HAPR group was 9.7% (9 cases), and the results showed that the risk of ISR in HAPR group was significantly higher than that in No-HAPR group. All the results showed that CMTM5 was significantly correlated with the risk of ISR in CAD patients (P < 0.05). CMTM5 overexpression inhibited the proliferation and migration ability of ECs (P < 0.05), PI3K/Akt signaling pathways were involved in the role of regulation on ECs.@*CONCLUSION@#Our results revealed that CMTM5 gene was closely related with ISR, CMTM5 overexpression may repress ECs proliferation and migration through regulating PI3K-Akt signaling.
Subject(s)
Humans , Chemokines , Coronary Artery Disease/surgery , Coronary Restenosis , Drug-Eluting Stents/adverse effects , Endothelial Cells , MARVEL Domain-Containing Proteins , Phosphatidylinositol 3-Kinases , Tumor Suppressor Proteins摘要
Objective To elucidate the correlation between the single nucleotide polymorphism ofCKLF-like MARVEL transmembrane domain containing member 5 (CMTM5) gene rs723840 and the occurrence of coronary artery disease (CAD). Methods The present study is a case-control study. A total of 1110 hospitalized patients in Shijitan Hospital were enrolled in this study. Patients were divided into CAD group (n=560) and control group (n=550). CAD were diagnosed by coronary angiography, which was defined as at least one blood vessel diameter stenosis ≥50% according to the result of coronary angiography. Genotypes were determined by polymerase chain reaction (PCR) and using sequencing analysis to detect rs723840 of CMTM5 gene. The proportions of genotype and allele of CMTM5 gene were analyzed. Results The genotype frequencies in rs723840 C>T of CMTM5 gene conformed well to the Hardy-Weinberg equilibrium in both CAD group and control group. Between the two groups, the genotypes frequency (CC, CT and TT) in CAD and control groups were 53.9%, 40.9%, 5.2% and 69.3%, 28.7%, 2.0%, respectively (P<0.001). T allele frequency was significantly higher than that in C allele frequency (25.6% vs. 16.4%, OR=1.566, 95%CI 1.325-1.850, P<0.001). After adjusted for the risk factors of age, gender, BMI, smoking, hypertension, diabetes and hyperlipidemia, logistic regression analysis results indicated that CMTM5 was the susceptibility factors of CAD, which showed significant correlation with CAD. Conclusions A significant correlation was found between CMTM5 gene rs723840 polymorphism and the occurrence of CAD, T allele carriers are closely related to the occurrence of CAD.
摘要
@# Objective: To evaluate the expression of CKLF-like MARVEL transmembrane domain containing member 6 (CMTM6) in lung adenocarcinoma tissues, and to explore its correlation with the clinicopathologic features and prognosis of patients. Methods: Eighty-six pairs of cancer tissues and para-cancer tissues from patients that pathologically confirmed with lung adenocarcinoma were collected during September 2004 and June 2009 at the Third Affiliated Hospital of Soochow University. The expression levels of CMTM6 in above mentioned tissues were detected by immunohistochemistry. Serum of 52 patients with confirmed lung adenocarcinoma was collected before and after surgery, and serum of 32 healthy subjects was also collected. The levels of CMTM6 and PD-L1 in peripheral blood before and after surgery were measured and analyzed by ELISA. Chi-square test was used to analyze the relationship between CMTM6 expression and clinicopathological features; Kaplan-Meier method and Log-Rank test were used to analyze the survival data of patients. Results: CMTM6 was widely expressed in lung adenocarcinoma tissues; 30% of the tumor tissues showed an up-regulation as compared with para-cancer tissues, and 70% showed no difference. CMTM6 expression was associated with clinical stage and distant metastasis (all P<0.05), but not significantly associated with age, gender, tumor size, and T stage (P>0.05). Kaplan-Meier survival analysis showed the survival rate of patients with high CMTM6 expression was significantly lower than those with stable expression (P=0.014), and among patients at stage Ⅲ, the survival rate of patients with high CMTM6 expression was significantly lower than those with stable CMTM6 expression (P=0.001). Cox regression model analysis of multiple factors showed CMTM6 expression was an independent risk factor for the prognosis of patients with lung adenocarcinoma. CMTM6 expression in pre-surgery serum, post-surgery serum and healthy donors’serum showed statistically significant differences (P<0.05), which was significantly correlated with tumor size and age of the patients. Spearman correlation analysis showed a significant correlation between serum CMTM6 and PD-L1 expression level (r=0.623, P<0.01). Conclusion: CMTM6 is an independent risk factor for the prognosis of lung adenocarcinoma patients. It plays an important role in the occurrence and development of lung adenocarcinoma and it is a potential tumor suppressor gene.
摘要
AIM:To investigate the effect of CKLF1-C19 polypeptide (C19) on differentiation of human lung fibroblast (LFB) into myofibroblast (MFB) induced by TGF-β. METHODS:LFBs were cultured and identified. LFBs were treated with TGF-β(5 μg/L) to establish the cell model of LFB differentiate into MFB. The LFBs were divided into 6 experimental groups including control group,TGF-β group,and TGF-β plus different doses(1,0.1,0.01,0.001 mg/L) C19 groups. The cell morphology,cell proliferation rate, and the expression of α smooth muscle actin (α-SMA) and collagen Ⅰ were observed. RESULTS:Human primary LFB was successfully cultured and was confirmed by the method of immunofluorescence. TGF-β at 5 μg/L induced proliferation and differentiation of LFB. The mRNA levels of α-SMA and collagen Ⅰ in TGF-β group were higher than that in control group(P<0.05).The cell proliferation rates,mRNA levels of α-SMA and collagen Ⅰ, and the protein expression of α-SMA in 0.01 mg/L+TGF-β group and 0.001 mg/L+TGF-β group were markedly lower than those in TGF-β group(P<0.05). CONCLUSION:C19 at 0.01 mg/L and 0.001 mg/L effectively inhibits differentiation of LFB into MFB induced by TGF-β, thus inhibiting the process of airway remodeling and fibrosis to some extent.
摘要
Objective To explore the acute toxicity effect of CKLF1-C19,a polypeptide of chemokine-like factor 1(CKLF1),on the KM mice. Methods A total of 40 KM mice,half male and half female,were randomly divided into 2 groups. The mice in the experimental group were injected with CKLF1-C19 at a dose of 25 mL/kg(100 μg/mL,1 mg/mL and 10 mg/mL)through the tail vein,and those in the control group received an equal volume of sterile saline solution. Changes in the body weight of the mice were recorded the day after treatment, and the general conditions of mice in the experimental group were observed closely and compared with the normal group. Then blood samples were taken from the abdominal aorta to measure liver and kidney function. Tissue samples of liver, kidney, spleen and lung were taken for histopathological examination by HE staining. Results In the maximum tolerance test,the mice of the two groups were in good condition, and their body weight was increased gradually, without significant difference between the experimental group and the control group(P > 0.05). There was no death within 14 days. The blood biochemical indexes of liver and kidney function showed no significant differences between the two groups(P > 0.05). The gross appearances of heart, liver,kidney,spleen and lung were normal in the two mouse groups, and the pathological examination with HE staining showed normal clear structure with no obvious changes in these organs of each group. Conclusions Our results demonstrate that CKLF1-C19 has no acute toxicity effect on mice.
摘要
Aim To investigate the role of chemokine-like factor 1 ( CKLF1 ) in SH-SY5 Y cell migration and its molecular regulatory mechanism. Methods SH-SY5Y cells were stimulated with CKLF1 for 0. 5 h, 2 h, 8 h and 24 h, respectively. The migration distance and the percentage of migration cells were recorded by CELLocate analysis. The phosphorylation of focal ad-hesion kinase ( FAK) at Tyr-397 site was detected by Western blot analysis. By chemotaxis assays, we con-firmed the chemotaxis of CKLF1. Furthermore, FAK inhibitor PF-573228 and PLCγ inhibitor U73122 were used for the research of molecular regulatory mecha-nisms involved. Results CKLF1 promoted cell migra-tion and induced a strong increase in the phosphoryla-tion level of FAK-pY397 , which were significantly at-tenuated by the presence of U73122 ( a specific inhibi-tor for PLCγ) . In addition, the chemotaxis of CKLF1 was obviously blocked by the FAK inhibitor PF-573228 . Conclusion CKLF1 induces SH-SY5 Y cell migration via PLCγ/FAK signaling pathway.
摘要
Objective To investigate the expression of CKLF-like MARVEL transmembrane (CMTM)domain-containing family in clear cell renal cell carcinoma(ccRCC)and its significance.Methods Seventy-five samples of ccRCC were collected,including 50 males and 25 females,mean age (59 ± 10)years.There were 34 cases in clinical stage Ⅰ,23 cases in stage Ⅱ,14 cases in stage Ⅲ and 4 cases in stage Ⅳ.The pathological differentiation was 3 cases of grade Ⅰ,1 case of grade Ⅰ-Ⅱ,35 cases of grade Ⅱ,10 cases of grade Ⅱ-Ⅲ,18 cases of grade Ⅲ,3 cases of grade Ⅲ-Ⅳ and 5 cases of grade Ⅳ.The expression of CMTM3 and CMTM5 proteins in 75 cases of ccRCC and corresponding adjacent normal kidney tissues was detected by tissue microarray and immunohistochemistry.Results The positive expression rate of CMTM3 and CMTM5 was 98.7％,97.3％ in the adjacent normal kidney tissues,and 44.0％,68.0％ in ccRCC tissues(P ＜ 0.05).The expression of CMTM3 and CMTM5 had no correlation with the gender,age,clinical staging and pathological differentiation(P ＞ 0.05).Conclusion CMTM3 and CMTM5 could be ccRCC suppressor genes,and their mutation or methylation might be an early event in the carcinogenesis of ccRCC,thus promise them to be potential biomarkers in early diagnosis.
摘要
Objective To study the effect and mechanism of CKLF-like Marvel transmembrane domain containing 5 (CMTMS) on prostate cancer cell proliferation,migration and invasion.Methods The inhibitory effects of CMTM5 on the migration of DU145 cells were studied in vitro by wound healing assay.The expression of the cell signal pathway PI3K-AKT protein was detected by Western blot.The inhibition of tumor growth was also studied in transplanted prostate cancer nude mice model treated with CMTM5 adenovirus.The expression of CMTM5 and ki-67 in transplanted prostate cancer tissue of the nude mice model was analyzed immunohisochemistically.Prostate tumor volume in the nude mice model and the proliferation were measured two weeksafter.injection..Results Wound healing assay showed that over-expression of CMTM5 can inhibit the migration of DU145 cells.The expression of pAKT and NF-kB was significantly decreased after the overexpression of CMTM5.The tumor volume (573.39 ± 175.24) mm3,weight (0.55 ± 0.11) g and proliferation index of prostate in CMTM5 orthotopic injection nude mice model were significantly smaller and decreased than those in the control group (1482.50 ± 327.86) mm3 and (1.31 ± 0.29) g (P ＜ 0.05).Conclusions Both in vitro and in vivo experiments demonstrate that overexpression of CMTM5 could suppress prostate cancer cell proliferation,migration and invasion.The effect may be conducted by PI3K-AKT signaling pathway.