| Esophageal squamous cell carcinoma(ESCC)is one of the leading malignant tumors in the worldwide,and its mortality ranks sixth in malignant tumors.Due to the lack of effective early diagnostic markers and the lack of clear molecular mechanism for the progression of ESCC.Unsatisfactory prognosis of ESCC patients were diagnosed at the first diagnosis at the middle and advanced stages.And lack of successful therapeutic strategies,so the overall five-year survival rate was only 15%-25%.Moreover,the molecular mechanism for ESCC remains largely unknown,especially concerning tumorigenesis.Thus,in-depth research on the molecular mechanism of ESCC,development of effective therapeutic targets,and search for effective diagnostic or prognostic markers for advanced ESCC patients is key to improve the efficacy and prognosis of ESCC patients.As a calcium ion-binding protein superfamily,the S100 protein family of more than 20 members is widely involved in multiple biological processes of various malignant tumors including proliferation,migration,invasion,angiogenesis,immune escape,and cell differentiation.At the same time,dysregulated expression of multiple members of the S100 family is a common feature of human cancers,with each type of cancer showing a unique S100 protein profile or signature.Moreover,many members are also important tumor diagnostic markers and targeted therapeutic targets.Among them,the family member S100A7 was firstly found in epithelial cells of psoriasis patients.Abnormal expression has been found in breast cancer,head and neck squamous cell carcinoma,pancreatic cancer,cervical cancer,lung cancer and many other tumors.And it is involved in multiple biological processes of tumorigenesis and progression,showing a high degree of tumor specificity.Previous studies showed,S100A7 is a calcium-binding protein expressed and secreted by epithelial cells.In the presence of calcium ions.S100A7 combines with target proteins to produce biological effects and participate in cell life activities.S100A7 modulates tumor cell proliferation,metastasis,angiogenesis and immune evasion by functioning both as intracellular Ca2+ sensors and as extracellular factors.However,the involvement of S100A7 in ESCC is poorly understood.Here,we aimed to investigate the role of S100A7 for ESCC.The data of TCGA ESCC were used to analyze the expression levels of S100 family members in ESCC tissues.Multiple S100 family members were found obviously upregulated in ESCC tissues compared to normal tissues via analyzing TCGA data.Among them,S100A7 ranked in the top 5 up-regulated genes.Moreover,there was a significant correlation with the tumor infiltrating M2 macrophages.Therefore,we conducted further research on the carcinogenic role of S100A7 in ESCC.The upregulation of S100A7 was further validated in our mRNA microarray data of 119 pair ESCC and adjacent normal tissues(p<0.001).Immunohistochemical analysis of 341 ESCC tissue and 233 adjacent normal tissue samples demonstrated that S100A7 protein was also significantly increased in ESCC tissues(p<0.001).Multivariate COX analysis found that S100A7 is an independent prognostic factor associated with poor prognosis of ESCC(p=0.026).Furthermore,the expression of S100A7 in the serum samples of esophageal patients and normal subjects was detected via ELISA,and the free S100A7 protein in the blood of ESCC patients was significantly increased(p<0.001),showing considerable diagnostic potential(AUC=0.790,95%CI:0.748-0.833).Gain and lose of function assays in vivo and vitro indicated that upregulated S100A7 could promote cell migration and proliferation.Mechanically,S100A7 exerts functions through both intracellular binding to JAB1;and then activates the downstream NF-κB,ErK and AKT signaling pathways.In addition,studies on exocrine S100A7 of ESCC indicated that extracellular free S100A7 could promote M2 macrophage infiltration in the tumor microenvironment,and M2 macrophage infiltration was significantly increased in patients with high S100A7 expression.In summary,our study revealed the biological function and molecular mechanism of S100A7 in the occurrence and development for esophageal squamous cell carcinoma for the first time,and clarified the role of S100A7 in the regulation of immune microenvironment.Furthermore,we evaluated the clinical value of S100A7 as a diagnostic and prognostic marker,providing new ideas for the diagnosis and treatment of esophageal squamous cell carcinomaObjective To study the biological function and clinicopathological correlation of TGFβ induced long non-coding RNA(lncRNA)TBULC in non-small cell lung cancer(NSCLC),and to analyze its application potential in clinical diagnosis and treatment.Methods RT-qPCR was used to detect the expression level of TBULC in NSCLC cells and tissues,and the correlation between TBULC expression level and clinicopathological features was analyzed.Cytoplasm/nuclear fractionation assay was performed to define the cellular localization of TBULC.Rapid amplification of cDNA ends(RACE)assay was performed to acquire the full-length sequence of TBULC.TBULC stable overexpression and knockdown cell clones were constructed by lentiviral packaging infection,and Transwell assay was used to explore the effect of TBULC on cell invasion and migration.Results TGFβ stimulation of NSCLC cell lines could significantly upregulate the expression level of nuclear localized lncRNA TBULC.Furthermore,RACE assay obtained the exact full-length sequence of TBULC is 1020 nucleotides and located on chromosome 15.Cell function experiments showed that TBULC play an important role in promoting metastasis in NSCLC.The invasion and migration ability of TBULC knockdown clones is significantly suppressed,while TBULC overexpression enhanced the invasion and migration ability of tumor cells.The expression level of TBULC in 106 pairs of NSCLC and adjacent normal tissues were analyzed and found that TBULC was highly expressed in tumor tissues and was an independent prognostic factor(p=0.030,OR=0.513(0.281-0.936)).Conclusion TGFβ-induced lncRNA TBULC is upregulated in NSCLC and promotes the invasion and migration of tumor cells.It is an independent prognostic factor and has potential to become a therapeutic and prognostic target. |
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