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SEMA3C Promotes Cervical Cancer Growth and Is Associated With Poor Prognosis.

ABSTRACT: Introduction: Aberrant activation of Semaphorin3C(SEMA3C) is widespread in human cancers. We aimed to analyze SEMA3C expression in cervical cancer and investigate the role of SEMA3C in cervical cancer and its underlying mechanism, which is important for exploring new therapeutic targets and prognostic factors. Materials and Methods: The expression of SEMA3C was examined in paraffin-embedded cervical cancer specimens. In vivo and in vitro assays were performed to validate the effect of SEMA3C on cervical cancer cell proliferation and p-ERK pathway activation. Gene Set Enrichment Analysis (GSEA) was performed using The Cancer Genome Atlas (TCGA) data set. Results: SEMA3C expression was associated with poor survival in both the TCGA cohort and our cohort. Silencing of SEMA3C suppressed cervical cancer cell proliferation, colony formation ability, and the activation of the p-ERK signaling pathway in vitro. SEMA3C depletion inhibited tumor growth in vitro. GSEA also showed that the epithelial mesenchymal transition (EMT), TGF? signaling pathway, angiogenesis, and extracellular matrix (ECM) receptor interactions are associated with a high SEMA3C expression phenotype. Conclusion: SEMA3C is correlated with poor prognosis of cervical cancer patients and promotes tumor growth via the activation of the p-ERK pathway.

SUBMITTER: Liu R

PROVIDER: S-EPMC6794562 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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SEMA3C Promotes Cervical Cancer Growth and Is Associated With Poor Prognosis.

Liu Ruoyan R Shuai Yanjie Y Luo Jingtao J Zhang Ze Z

Frontiers in oncology 20191009

Introduction: Aberrant activation of Semaphorin3C(SEMA3C) is widespread in human cancers. We aimed to analyze SEMA3C expression in cervical cancer and investigate the role of SEMA3C in cervical cancer and its underlying mechanism, which is important for exploring new therapeutic targets and prognostic factors. Materials and Methods: The expression of SEMA3C was examined in paraffin-embedded cervical cancer specimens. In vivo and in vitro assays were performed to valid ...[more]

PMID: 31649890

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Project description:BackgroundThe pathogenesis and developmental mechanism of early-stage (FIGO 2009 IA2-IIA2) cervical cancer (CC) remain unclear. Seeking novel molecular biomarkers based on The Cancer Genome Atlas (TCGA) will facilitate the understanding of CC pathogenesis and help evaluate early-stage CC prognosis.MethodsTo identify prognosis-related genes in early-stage CC, we analyzed TCGA mRNA-seq data and clinical data by univariate Cox and Kaplan-Meier plotter analyses. Differential expression analysis identified upregulated genes in early-stage CC. Combined with the genes correlated with unfavorable prognosis, we selected desmoglein-2 (DSG2) for further investigation. To detect DSG2 expression in early-stage CC, we used immunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR) and western blotting. The relationship between the expression of DSG2 and clinical features was analyzed by the Chi square test. Cox analysis was applied to assess the relationship between CC overall survival (OS) and risk factors. The correlations between DSG2 expression and CC cell line proliferation and migration were investigated with Cell Counting Kit-8 (CCK-8) and migration assays.ResultsThere were 416 prognosis-related genes in early-stage CC. DSG2, matrix metallopeptidase 1 (MMP1), carbonic anhydrase IX (CA9), homeobox A1 (HOXA1), and serine protease inhibitor B3 (SERPINB3) were upregulated in early-stage CC compared with adjacent noncancerous tissue (ANT) and correlated with unfavorable prognosis. Among them, DSG2 was most significantly correlated with patient survival. Coexpression analysis indicated that DSG2 was probably involved in cell division, positive regulation of transferase activity, positive regulation of cell migration, EGFR upregulation pathway and regulation of lymphangiogenesis. IHC, qRT-PCR and western blotting showed that DSG2 expression was higher in CC than in normal tissue. Significant correlations were identified between DSG2 expression and several aggressive clinical features, including pelvic lymph node metastasis (PLNM). Multivariate Cox analysis showed that DSG2 and PLNM were independent prognostic factors for OS. DSG2 knockdown inhibited CC cell proliferation and migration.ConclusionsDSG2 is a biomarker that promotes tumor proliferation and metastasis and is correlated with poor prognosis in early-stage CC.

Project description:Currently, the occurrence and mortality rate of cervical cancer is high, particularly in low-to-middle-income countries. Therefore, the development of novel diagnostic and treatment strategies for cervical cancer is urgently required. The aim of the present study was to assess the prognostic significance of fibronectin type III domain containing 3B (FNDC3B) expression in patients with cervical cancer and to determine the underlying mechanism of FNDC3 in tumor development. Analysis of the ONCOMINE database revealed that FNDC3B was significantly upregulated in cervical cancer tissue compared with normal tissue. Additionally, FNDC3B expression data and the clinical characteristics of patients with cervical cancer were obtained from the cBioPortal database. Correlations between FNDC3B expression and overall survival were subsequently investigated. The results revealed that increased FNDC3B expression was significantly correlated with a lower overall survival in patients with cervical cancer. A co-expression network was subsequently constructed to elucidate the function of FNDC3B in cervical cancer. Co-expression genes for FNDC3B were obtained from the cBioPortal database and were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. The results demonstrated that the genes were enriched in pathways associated with migration, invasion, endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Furthermore, immunofluorescence results obtained from the Human Protein Atlas revealed that the FNDC3B protein was localized to the ER. The results revealed that upregulated FNDC3B expression may be a biomarker for poor prognosis for patients with cervical cancer. Additionally, the results revealed that FNDC3B may serve an oncogenic role in cancer development via ER stress, UPR, cell migration and invasion. However, further studies are required to determine the exact molecular mechanism of FNDC3B in the development of cervical cancer and to assess its potential as a novel therapeutic target for the treatment of this disease.

Project description:The chemokine CCL22 recruits regulatory T (T-reg) cells into tumor tissues and is expressed in many human tumors. However, the prognostic role of CCL22 in cervical cancer (CC) has not been determined. This study retrospectively analyzed the clinical significance of the expression of CCL22 and FOXP3 in 230 cervical cancer patients. Immunohistochemical staining analyses of CCL22 and FOXP3 were performed with a tissue microarray. Double immunofluorescence staining, cell coculture, and ELISA were used to determine CCL22 expressing cells and mechanisms. The higher number of infiltrating CCL22+ cells (CCL22high) group was associated with lymph node metastasis (p = 0.004), Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stages (p = 0.010), therapeutic strategies (p = 0.007), and survival status (p = 0.002). The number of infiltrating CCL22+ cells was positively correlated with that of infiltrating FOXP3+ cells (r = 0.210, p = 0.001). The CCL22high group had a lower overall survival rate (OS), compared to the CCL22low group (p = 0.001). However, no significant differences in progression free survival (PFS) were noted between the two groups. CCL22high was an independent predictor of shorter OS (HR, 4.985; p = 0.0001). The OS of the combination group CCL22highFOXP3high was significantly lower than that of the combination group CCL22lowFOXP3low regardless of the FIGO stage and disease subtype. CCL22highFOXP3high was an independent indictor of shorter OS (HR, 5.284; p = 0.009). The PFS of group CCL22highFOXP3high was significantly lower than that of group CCL22lowFOXP3low in cervical adenocarcinoma, but CCL22highFOXP3high was not an independent indicator (HR, 3.018; p = 0.068). CCL22 was primarily expressed in M2-like macrophages in CC and induced by cervical cancer cells. The findings of our study indicate that cervical cancer patients with elevated CCL22+ infiltrating cells require more aggressive treatment. Moreover, the results provide a basis for subsequent, comprehensive studies to advance the design of immunotherapy for cervical cancer.

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SEMA3C Promotes Cervical Cancer Growth and Is Associated With Poor Prognosis.

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SEMA3C Promotes Cervical Cancer Growth and Is Associated With Poor Prognosis.

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