Gene Summary

Gene:VIP; vasoactive intestinal peptide
Aliases: PHM27
Summary:The protein encoded by this gene belongs to the glucagon family. It stimulates myocardial contractility, causes vasodilation, increases glycogenolysis, lowers arterial blood pressure and relaxes the smooth muscle of trachea, stomach and gall bladder. The protein also acts as an antimicrobial peptide with antibacterial and antifungal activity. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Nov 2014]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:VIP peptides
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: VIP (cancer-related)

Shao K, Wang Y, Xue Q, et al.
Clinicopathological features and prognosis of ciliated muconodular papillary tumor.
J Cardiothorac Surg. 2019; 14(1):143 [PubMed] Free Access to Full Article Related Publications
BACKGROUNDS: The pulmonary ciliated muconodular papillary tumor (CMPT) is a very rare tumor with only several case reports in published literatures, and its clinicopathological features, standard treatment methods and prognosis has not been well defined.
METHODS: Two cases of CMPT diagnosed and treated in our hospital and 39 cases reported in the published literature were analyzed retrospectively.
RESULTS: The cohort of 41 CMPT patients comprised of 20 males and 21 females, aged 9-84 years. The diameter of the primary tumor was 0.3-4.5 cm. Most of these lesions were subsolid nodules, as observed on computed tomography and easily misdiagnosed as early lung adenocarcinoma. Tumors of 26 patients were stained by immunohistochemistry method, which revealed that CK7, CEA, and TTF-1 were positive and CK20 was negative in most patients. The results of gene alternation demonstrated mutations in EGFR, KRAS, and BRAF and ALK rearrangements in CMPT. All the patients underwent surgical treatment and did not receive postoperative adjuvant therapy. The follow-up duration was 0-120 months, and no case of tumor recurrence was found until the final follow-up.
CONCLUSIONS: The incidence of CMPT was low and rate of image misdiagnosis high. Immunohistochemistry is helpful for accurate diagnosis of CMPT. Sub-lobectomy may be proper and adjuvant treatment should be avoided since the disease is now prone to benign lesions. Furthermore, since the biological behavior of this tumor is not yet fully elucidated, additional case data are essential for accurate conclusions.

Shen ML, Xiao A, Yin SJ, et al.
Associations between UGT2B7 polymorphisms and cancer susceptibility: A meta-analysis.
Gene. 2019; 706:115-123 [PubMed] Related Publications
BACKGROUND: UGT2B7 was recently acknowledged as a new critical enzyme involved in biotransformation of a variety of carcinogens, whose function was reported to be significantly associated with its encoding gene (UGT2B7) polymorphisms. However, results regarding the associations between single nucleotide polymorphisms (SNPs) of UGT2B7 and cancer risk still remained controversial. Therefore, a meta-analysis was conducted to further elucidate the role of UGT2B7 SNPs on cancer susceptibilities.
METHODS: PubMed, EMBASE, Cochrane library, Chinese National Knowledge Infrastructure (CNKI), Technology of Chongqing (VIP) and Wan Fang Database were searched for eligible studies until March 2019. All analysis was carried out using the Review Manager 5.3 software. Subgroup analyses were performed by cancer types, ethnicity or source of controls.
RESULTS: 13 studies with a total of 7688 cancer cases and 11,281 controls were included in this meta-analysis. The results showed that UGT2B7 rs7439366 increased the colorectal cancer risk in dominant model (OR = 0.76, 95% CI = 0.61-0.95, P = 0.02). However, as for the rs7435335 and rs12233719, we did not find their associations with cancer risk in all genetic models. In addition, the rs7441774 was found to be associated with breast cancer risk and significantly reduced papillary thyroid cancer risk in rs3924194 was also observed. Nevertheless, these findings remained to be further proven in future studies since these 2 SNPs were only respectively involved in 1 study.
CONCLUSION: This meta-analysis confirmed the association of UGT2B7 rs7439366 with colorectal cancer risk, which may be a potential promising biomarker for prediction of colorectal cancer risk.

Sun L, Wang Y, Wang L, et al.
Resolvin D1 prevents epithelial-mesenchymal transition and reduces the stemness features of hepatocellular carcinoma by inhibiting paracrine of cancer-associated fibroblast-derived COMP.
J Exp Clin Cancer Res. 2019; 38(1):170 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cancer stem cells (CSCs) require stromal signals for maintaining pluripotency and self-renewal capacities to confer tumor metastasis. Resolvin D1 (RvD1), an endogenous anti-inflammatory lipid mediator, has recently been identified to display anti-cancer effects by acting on stroma cells. Our previous study reveals that hepatic stellate cells (HSCs)-derived cartilage oligomeric matrix protein (COMP) contributes to hepatocellular carcinoma (HCC) progression. However, whether RvD1 inhibits paracrine of cancer-associated fibroblasts (CAFs)-derived COMP to prevent epithelial-mesenchymal transition (EMT) and cancer stemness in HCC remains to be elucidated.
METHODS: CAFs were isolated from HCC tissues. Direct and indirect co-culture models were established to analyze the interactions between HCC cells and CAFs in the presence of RvD1 in vitro. The transwell and tumor sphere formation assays were used to determine invasion and stemness of HCC cells. The subcutaneous tumor formation and orthotopic liver tumor models were established by co-implantation of CAFs and HCC cells to evaluate the role of RvD1 in vivo. To characterize the mechanism of RvD1 inhibited paracrine of COMP in CAFs, various signaling molecules were analyzed by ELISA, western blotting, reactive oxygen species (ROS) detection, immunofluorescence staining, dual luciferase reporter assay and chromatin immunoprecipitation assay.
RESULTS: Our data revealed that RvD1 treatment can impede the CAFs-induced cancer stem-like properties and the EMT of HCC cells under co-culture conditions. In vivo studies indicated that RvD1 intervention repressed the promoting effects of CAFs on tumor growth and metastasis of HCC. Furthermore, RvD1 inhibited CAF-induced EMT and stemness features of HCC cells by suppressing the secretion of COMP. Mechanistically, formyl peptide receptor 2 (FPR2) receptor mediated the suppressive effects of RvD1 on COMP and forkhead box M1 (FOXM1) expression in CAFs. Notably, RvD1 impaired CAF-derived COMP in a paracrine manner by targeting FPR2/ROS/FOXM1 signaling to ultimately abrogate FOXM1 recruitment to the COMP promoter.
CONCLUSION: Our results indicated that RvD1 impaired paracrine of CAFs-derived COMP by targeting FPR2/ROS/FOXM1 signaling to repress EMT and cancer stemness in HCC. Thus, RvD1 may be a potential agent to promote treatment outcomes in HCC.

Zhang J, Hou L, Liang R, et al.
CircDLST promotes the tumorigenesis and metastasis of gastric cancer by sponging miR-502-5p and activating the NRAS/MEK1/ERK1/2 signaling.
Mol Cancer. 2019; 18(1):80 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Accumulating evidence shows that, the dysregulation of circular RNAs (circRNAs) is associated with the progression of multiple malignancies. But, the underlying mechanisms by which has_circ_0032627 (circDLST) contributed to gastric cancer (GC) remain undocumented.
METHODS: The expression and cellular localization of circDLST and its association with clinicopathological characteristics and prognosis in patients with GC was analysed by using fluorescence in situ hybridization. Gain- and loss-of-function experiments as well as a subcutaneous xenograft tumor model and a liver metastasis model from orthotopic implantation of GC tissues were conducted to assess the role of circDLST in GC cells. CircDLST specific binding with miR-502-5p was confirmed by dual luciferase gene report, RNA immunoprecipitation (RIP) assays and RIP-miRNA expression profiling. qRT-PCR and Western blot analysis was used to detect the effects of circDLST on miR-502-5p-mediated NRAS/MEK1/ERK1/2 signaling in GC cells.
RESULTS: The expression levels of circDLST were dramatically elevated in GC tissues as compared with the adjacent normal tissues, and acted as an independent prognostic factor of poor survival in patients with GC. Knockdown of circDLST inhibited the cell viability, colony formation, DNA synthesis, cell invasion and liver metastasis in vitro and in vivo, whereas overexpression of circDLST had the opposite effects. Furthermore, circDLST was co-localized with miR-502-5p in the cytoplasm of GC cells, and acted as a sponge of miR-502-3p in GC cells, which abrogated the tumor promoting effects of circDLST by inactivating the NRAS/MEK1/ERK1/2 signaling in GC cells.
CONCLUSION: CircDLST promotes the tumorigenesis and metastasis of GC cells by sponging miR-502-5p to activate the NRAS/MEK1/ERK1/2 signaling.

Jiang H, Yang Z, Song Z, et al.
γδ T cells in hepatocellular carcinoma patients present cytotoxic activity but are reduced in potency due to IL-2 and IL-21 pathways.
Int Immunopharmacol. 2019; 70:167-173 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is the most common primary liver carcinoma and has one of the highest mortality rates of all cancers. The γδ T cells could infiltrate HCC and have demonstrated potent tumor-killing capacity. Here, we found that in peripheral blood, the vast majority of γδ T cells were Vδ2 T cells. In HCC patients, the frequency of Vδ2 T cells was significantly lower than in controls. γδ T cells that were harvested directly ex vivo possessed very limited capacity to eliminate Zol-loaded HCC cell lines, even at a high effector to target ratio. In vitro expansion with Zol could significantly increase the capacity of γδ T cells to eliminate HCC cell lines. But even with in vitro expansion, the γδ T cells from HCC patients presented significantly lower cytotoxic capacity than the γδ T cells from healthy individuals. The expression of IL-2 and IL-21 by γδ T cells was significantly lower in HCC patients than in control volunteers. Supplementing recombinant human IL-2 and IL-21 in the in vitro expansion culture increased the cytotoxic capacity of γδ T cells. In addition, the frequency of PD-1

He D, Wu Z, He J, et al.
Up-regulation of C5orf34 promotes lung adenocarcinoma migration and is correlated with worse prognosis.
Gene. 2019; 696:47-53 [PubMed] Related Publications
OBJECTIVE: This study aimed to investigate the biological role of C5orf34 in Lung adenocarcinoma (LAD) and the mechanism of such role.
METHODS: The mRNA expression of C5orf34 was analyzed using student's t-test based on the data obtained from TCGA database. Kaplan-Meier analysis was performed to evaluate the prognosis value of C5orf34. Chi-square (χ
RESULTS: C5orf34 expression was enhanced in LAD and positively correlated with poor prognosis in patients with LAD. χ
CONCLUSION: Our results firstly revealed that C5orf34 might play a facilitating role in LAD development and progression by regulating MAPK signaling pathway. Furthermore, our data implied that C5orf34 may be a potential predictor and treatment target for LAD.

Yang H, Wu J, Zhang J, et al.
Integrated bioinformatics analysis of key genes involved in progress of colon cancer.
Mol Genet Genomic Med. 2019; 7(4):e00588 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Colon cancer is one of most malignant cancers around worldwide. Nearly 20% patients were diagnosed at colon cancer with metastasis. However, the lack of understanding regarding its pathogenesis brings difficulties to study it.
METHODS: In this study, we acquired high-sequence data from GEO dataset, and performed integrated bioinformatic analysis including differently expressed genes, gene ontology and Kyoto Encyclopedia of Genes and Genomes pathways analysis, protein-protein analysis, survival analysis to analyze the development of colon cancer.
RESULTS: By comparing the colon cancer tissues with normal colon tissues, 109 genes were dysregulated; among them, 83 genes were downregulated and 26 genes were upregulated. Two clusters were founded based on the STRING database and MCODE plugin of cytoscape software. Then, six genes with prognostic value were filtered out in UALCAN website.
CONCLUSION: We found that SPP1, VIP, COL11A1, CA2, ADAM12, INHBA could provide great significant prognostic value for colon cancer.

Dong Z, Wang Y
LncRNA BLACAT1 accelerates the proliferation and migration of osteosarcoma cells through regulating STAT3.
Pathol Res Pract. 2019; 215(3):571-579 [PubMed] Related Publications
BACKGROUND: Long non-coding RNAs (lncRNAs) have been reported in human cancers as regulators for biological processes. LncRNA bladder cancer associated transcript 1 (BLACAT1) has been found to exert oncogenic function in cervical cancer and lung cancer. However, whether it can regulate the biological processes in osteosarcoma (OS) is still unclear. This study aims to examine the potential effect of dysregulated BLACAT1 on the progression of OS.
METHODS: The expression pattern of BLACAT1 in OS tissues and cell lines was detected by qRT-PCR assay. Gain or loss-of function assays were designed and conducted to determine the effect of BLACAT1 overexpression or knockdown on the OS cell proliferation, apoptosis, invasion and migration. RNA pull-down assay and western blot analysis were performed to identify the relationship between BLACAT1 and signal transducer and activator of transcription 3 (STAT3).
RESULTS: BLACAT1 was upregulated in OS tissues and cells. Upregulation of BLACAT1 predicted unfavorable prognosis for patients with OS. Downregulation of BLACAT1 inhibited cell proliferation and invasion, whereas upregulation of BLACAT1 accelerated cell proliferation and invasion. More importantly, BLACAT1 could interact with STAT3 and regulat the phosphorylation of STAT3.
CONCLUSIONS: LncRNA BLACAT1 contributes to the proliferation and migration of OS cells by regulating STAT3.

Chen L, Nan A, Zhang N, et al.
Circular RNA 100146 functions as an oncogene through direct binding to miR-361-3p and miR-615-5p in non-small cell lung cancer.
Mol Cancer. 2019; 18(1):13 [PubMed] Free Access to Full Article Related Publications
Circular RNAs are widely expressed in eukaryotic cells and associated with cancer. However, limited studies to date have focused on the potential role of circRNAs in progression of lung cancer. Data from the current investigation showed that circRNA 100146 is highly expressed in non-small cell lung cancer (NSCLC) cell lines and the chemically induced malignant transformed bronchial cell line, 16HBE-T, as well as 40 paired tissue samples of NSCLC. Suppression of circRNA 100146 inhibited the proliferation and invasion of cells and promoted apoptosis. Furthermore, circRNA 100146 could interact with splicing factors and bind miR-361-3p and miR-615-5p to regulate multiple downstream mRNAs. Our collective findings support a role of circRNA 100146 in the development of NSCLC and further demonstrate endogenous competition among circRNA 100146, SF3B3 and miRNAs, providing novel insights into the mechanisms underlying non-small cell lung cancer.

Xiao Z, Wang CQ, Zhou MH, et al.
The Antitumor Immunity and Tumor Responses of Chemotherapy with or without DC-CIK for Non-Small-Cell Lung Cancer in China: A Meta-Analysis of 28 Randomized Controlled Trials.
J Immunol Res. 2018; 2018:9081938 [PubMed] Free Access to Full Article Related Publications
Objective: DC-CIK therapy included DC-CIK cells and Ag-DC-CIK cells. To further confirm whether DC-CIK reconstructs the antitumor immunity and improves the tumor responses and reveals its optimal usage and combination with chemotherapy, we systematically reevaluated all the related studies.
Materials and Methods: All studies about DC-CIK plus chemotherapy for NSCLC were collected from the published and ongoing database as CBM, CNKI, VIP, Wanfang, ISI, Embase, MEDLINE, CENTRAL, WHO-ICTRP, Chi-CTR, and US clinical trials (established on June 2017). We evaluated their methodological bias risk according to the Cochrane evaluation handbook of RCTs (5.1.0), extracted data following the predesigned data extraction form, and synthesized the data using meta-analysis.
Results: We included 28 RCTs (phase IV) with 2242 patients, but most trials had unclear bias risk. The SMD and 95% CI of meta-analysis for CD3
Conclusions: DC-CIK therapy can simultaneously improve the antitumor immunity and tumor responses. DC-CIK therapy, especially DC-CIK cells, can improve antitumor immunity through increasing the T lymphocyte subsets, CIK cell, and NK cells in peripheral blood. The one cycle to two cycles may be optimal cycle, and the NP or GP may be optimal combination.

Xu H, Wang C, Song H, et al.
RNA-Seq profiling of circular RNAs in human colorectal Cancer liver metastasis and the potential biomarkers.
Mol Cancer. 2019; 18(1):8 [PubMed] Free Access to Full Article Related Publications
In this study, the secondary sequencing was used to profile circRNA expression in the tissue samples from three CRC patients with liver metastasis and three matched CRC patients. After verified some candidates in another 40 CRC and CRC-m samples by qRT-PCR, we further demonstrated that circRNA_0001178 and circRNA_0000826 were significantly upregulated in CRC-m tissues, and both of them had the potential for diagnosing liver metastases from colorectal cancer. Finally, the networks of circRNA-miRNA-mRNA base on these two circRNAs were constructed respectively. This study showed that differentially expressed circRNAs were existed between the tissue samples from colorectal cancer patients with and without liver metastasis. And also suggested that circRNA_0001178 and circRNA_0000826 may serve as a potential diagnostic biomarker for liver metastases from colorectal cancer.

Zhang L, Wang L, Wang Y, et al.
LncRNA KTN1-AS1 promotes tumor growth of hepatocellular carcinoma by targeting miR-23c/ERBB2IP axis.
Biomed Pharmacother. 2019; 109:1140-1147 [PubMed] Related Publications
Long non-coding RNAs (lncRNAs) are critical regulators in the tumorigenesis and metastasis of hepatocellular carcinoma (HCC). LncRNA KTN1 antisense RNA 1 (KTN1-AS1) has been reported to play an important role in colorectal cancer and correlates with unfavorable clinical outcomes of head and neck squamous cell carcinoma. However, the clinical significance and functional role of KTN1-AS1 in HCC are still unclear. Here, we found that KTN1-AS1 was a highly expressed lncRNA in HCC according to public available databases and our HCC cohort. Further analyses revealed that higher expression of KTN1-AS1 was observed in HCC tissues with large tumor size, high tumor grade and advanced TNM stage. Analysis of survival data indicated that high KTN1-AS1 expression was prominently correlated with poor clinical outcomes of HCC patients. Functionally, KTN1-AS1 knockdown suppressed cell proliferation and colony formation, and increased apoptosis of SMMC-7721 cells in vitro. Furthermore, silencing of KTN1-AS1 restrained tumor growth of HCC in vivo. Conversely, forced expression of KTN1-AS1 facilitated Huh7 cell proliferation and inhibited apoptosis. Mechanistically, KTN1-AS1 inversely regulated miR-23c abundance in HCC cells. Further evidence supported that KTN1-AS1 acted as a competing endogenous RNA (ceRNA) by directly sponging miR-23c in HCC cells. Interestingly, erbb2 interacting protein (ERBB2IP), a known target of miR-23c, was positively regulated by KTN1-AS1 and its restoration reversed KTN1-AS1 knockdown attenuated HCC cell growth. To conclude, our study sheds light on the novel function and underlying mechanism of KTN1-AS1 in HCC, which may accelerate the development of cancer therapy.

Li Z, Li Y, Fu J, et al.
Clinical utility of microRNA-451 as diagnostic biomarker for human cancers.
Biosci Rep. 2019; 39(1) [PubMed] Free Access to Full Article Related Publications
We conducted comprehensive analyses to assess the diagnostic ability of miRNA-451 in cancers. A systematic online search was conducted in PubMed, Web of Science, China's national knowledge infrastructure, and VIP databases from inception to July 31, 2017. The bivariate random effect model was used for calculating sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under cure (AUC). The whole pooled sensitivity and specificity were 0.85 (0.77-0.90) and 0.85 (0.78-0.90) with their 95% confidence interval (95%CI), respectively. The pooled AUC was 0.91 (95%CI: 0.89-0.94). Positive likelihood ratio was 5.57 (95%CI: 3.74-8.31), negative likelihood ratio was 0.18 (95%CI: 0.11-0.28), and diagnostic odds ratio was 31.33 (95%CI: 15.19-64.61). Among Asian population, the sensitivity and specificity were 0.85 (95%CI: 0.77-0.91) and 0.86 (95%CI: 0.78-0.91), respectively. The positive likelihood ratio and negative likelihood ratio were 5.87 (95%CI: 3.78-9.12) and 0.17 (95%CI: 0.11-0.28). The diagnostic odds ratio and AUC were 34.31 (15.51-75.91) and 0.92 (0.89-0.94). The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and AUC for digestive system cancer were 0.83, 0.88, 6.87, 0.20, 35.13, and 0.92, respectively. The other cancers were 0.87, 0.81, 4.55, 0.16, 28.51, and 0.90, respectively. For sample source, the results still remain consistent. Our results indicated miRNA-451 has a moderate diagnostic ability for cancers, and could be a potential early screening biomarker, and considered as an adjuvant diagnostic index when being combined with other clinical examinations.

Wang H, Chen W, Jin M, et al.
CircSLC3A2 functions as an oncogenic factor in hepatocellular carcinoma by sponging miR-490-3p and regulating PPM1F expression.
Mol Cancer. 2018; 17(1):165 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Non-coding RNAs (ncRNAs) have been reported to participate in tumor progression by regulating gene expression. Previous studies showed that protein phosphatase Mg2
METHODS: The association between PPM1F or miR-490-3p expression and clinicopathological features and prognosis in patients with HCC was analyzed by TCGA RNA-sequencing data. CircSLC3A2 was identified to bind with miR-490-3p by bioinformatic analysis, and the binding sites between miR-490-3p and PPM1F or circSLC3A2 were confirmed by dual luciferase report and RNA immunoprecipitation (RIP) assays. The localization and clinical significance of miR-490-3p and circSLC3A2 in patients with HCC were investigated by fluorescence in situ hybridization (FISH). MTT, Agar, and Transwell assays were conducted to evaluate the effects of miR-490-3p or circSLC3A2 on cell proliferation and invasive potential.
RESULTS: The expression of PPM1F or miR-490-3p was associated with poor survival and tumor recurrence, and acted as an independent prognostic factor in patients with HCC. Re-expression of miR-490-3p inhibited HCC cell proliferation and invasion by targeting PPM1F, but its inhibitor reversed these effects. Moreover, circSLC3A2, predominantly localized in the cytoplasm, exhibited an oncogenic role by sponging miR-490-3p and regulating PPM1F expression, and harbored a positive correlation with poor survival in patients with HCC.
CONCLUSION: CircSLC3A2 acts as an oncogenic factor in HCC by sponging miR-490-3p and regulating PPM1F expression.

Li D, Xiao L, Ge Y, et al.
High expression of Tob1 indicates poor survival outcome and promotes tumour progression via a Wnt positive feedback loop in colon cancer.
Mol Cancer. 2018; 17(1):159 [PubMed] Free Access to Full Article Related Publications
Tob1, a Tob/BTG anti-proliferative protein family member, functions as a tumour suppressor in many cancers. Here, we reveal a unique oncogenic role of Tob1 in colon cancer. Tob1 expression was upregulated during colon cancer progression, was significantly correlated with tumour size and tumour differentiation, and was a prognostic indicator of colon cancer. Unlike in other cancers, where nuclear Tob1 performs anticancer activity, Tob1 is predominantly localized in the cytosol of colon cancer cells, where this protein binds and stabilizes β-catenin to activate Wnt/β-catenin signalling, which in turn enhances Tob1 expression, thus forming a positive feedback loop to promote cell proliferation. Moreover, Tob1 deficiency led to reduced tumourigenesis in AOM/DSS-treated and Apc

Wang F, Zhao L, Zhang J, et al.
Biosci Rep. 2018; 38(6) [PubMed] Free Access to Full Article Related Publications
One of the treatment failures for colorectal cancer (CRC) is resistance to chemotherapy drugs. miRNAs have been demonstrated to be a new regulator of pathobiological processes in various tumors. While few studies have explored the specific role of

Kong D, Li C, Yang Q, et al.
Long noncoding RNA LSINCT5 acts as an oncogene via increasing EZH2-induced inhibition of APC expression in osteosarcoma.
Biochem Biophys Res Commun. 2018; 507(1-4):193-197 [PubMed] Related Publications
Long noncoding RNAs (lncRNAs) are recognized as a class of critical regulators in various tumors. Recently, lncRNA LSINCT5 has been reported to promote the progression of bladder cancer, ovarian cancer, gastric cancer, and breast cancer. However, the biological function of LSINCT5 remains elusive in osteosarcoma (OS). In our study, we found that LSINCT5 was significantly upregulated in OS tissues than in adjacent normal tissues. Additionally, the expression of LSINCT5 was inversely associated with the prognosis of patients with OS. LSINCT5 knockdown dramatically inhibited OS cell proliferation in vitro and tumor growth in vivo. Mechanistic exploration revealed that LSINCT5 interacted with EZH2 to suppress the expression of APC, a negative regulator of the Wnt/β-catenin pathway. Moreover, rescue assays suggested that LSINCT5 exerted oncogenic roles by partially inhibiting APC expression in OS. In summary, our study demonstrated that LSINCT5 was a promising candidate for OS prognosis and therapy.

Liu A, Zeng S, Lu X, et al.
Overexpression of G2 and S phase-expressed-1 contributes to cell proliferation, migration, and invasion via regulating p53/FoxM1/CCNB1 pathway and predicts poor prognosis in bladder cancer.
Int J Biol Macromol. 2019; 123:322-334 [PubMed] Related Publications
Bladder cancer is one of the most common urogenital tumors worldwide. The specific function and molecular mechanism of GTSE1 in bladder cancer remain unknown. In the present study, real-time quantitative polymerase chain reaction and Western blotting were used to identify GTSE1 expression in bladder cancer tissues and cells, and immunohistochemical assays were conducted to investigate GTSE1 expression in tissue microarray. Regression analyses explored the relationship between GTSE1 expression and pathological characteristics. A series of functional tests were performed to observe the effects of GTSE1 knockdown or overexpression, and the related mechanism was also performed. GTSE1 expression was significantly higher in bladder cancer tissues; overexpression of GTSE1 was positively associated with disease recurrence history, lymph node invasion, and progression. Patients with higher GTSE1 expression were more likely to experience shorter survival time, and GTSE1 expression served as a prognostic factor for the disease progression. Knockdown of GTSE1 obviously suppressed the proliferation, migration, and invasion capacity whereas increasing GTSE1 led to the opposite trend, which suggested that GTSE1 could serve as a potential therapeutic target for bladder cancer. GTSE1 overexpression in bladder cancer might participate in the regulation of FoxM1/CCNB1 expression via the induction of the transfer of p53 to cytoplasm.

Ti D, Niu Y, Wu Z, et al.
Genetic engineering of T cells with chimeric antigen receptors for hematological malignancy immunotherapy.
Sci China Life Sci. 2018; 61(11):1320-1332 [PubMed] Related Publications
The host immune system plays an instrumental role in the surveillance and elimination of tumors by recognizing and destroying cancer cells. In recent decades, studies have mainly focused on adoptive immunotherapy using engineered T cells for the treatment of malignant diseases. Through gene engraftment of the patient's own T cells with chimeric antigen receptor (CAR), they can recognize tumor specific antigens effectively and eradicate selectively targeted cells in an MHC-independent fashion. To date, CAR-T cell therapy has shown great clinical utility in patients with B-cell leukemias. Owing to different CAR designs and tumor complex microenvironments, genetically redirected T cells may generate diverse biological properties and thereby impact their long-term clinical performance and outcome. Meanwhile some unexpected toxicities that result from CAR-T cell application have been examined and limited the curative effects. Diverse important parameters are closely related with adoptively transferred cell behaviors, including CAR-T cells homing, CAR constitutive signaling, T cell differentiation and exhaustion. Thus, understanding CARs molecular design to improve infused cell efficacy and safety is crucial to clinicians and patients who are considering this novel cancer therapeutics. In this review, the developments in CAR-T cell therapy and the limitations and perspectives in optimizing this technology towards clinical application are discussed.

Yi F, Shi X, Pei X, Wu X
Tumor necrosis factor-alpha-308 gene promoter polymorphism associates with survival of cancer patients: A meta-analysis.
Medicine (Baltimore). 2018; 97(45):e13160 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Tumor necrosis factor-alpha (TNF-α) is involved in cancer pathogenesis, and TNF-α-308G>A, a single-nucleotide polymorphism, is associated with cancer prognosis; however, different studies have reported inconsistent results. This meta-analysis aimed to determine the correlation between TNF-α-308G>A polymorphism and the survival of cancer patients.
METHODS: PubMed, Web of Science, Embase, Wanfang database, VIP database, and China National Knowledge Infrastructure database were used to obtain articles on association between TNF-α-308G>A polymorphism and cancer survival, published until April 2018. A meta-analysis was carried out using Stata 12.0 software to determine the pooled hazard ratio (HR) and 95% confidence intervals (95% CI). Furthermore, publication bias was assessed, and sensitivity analysis was performed to validate the analysis.
RESULTS: In total, 13 retrospective cohort studies including 2559 cancer patients were reviewed to estimate the association between TNF-α-308G>A polymorphism and overall survival (OS) of cancer patients. The pooled results suggested that within TNF-α-308G>A polymorphism, genotypes GA+AA/GG (HR = 1.39, 95% CI: 0.90-2.14, P < .001, I = 78.1%), GA/GG (HR = 1.06, 95% CI: 0.83-1.36, P = .072, I = 53.5%), and AA/AG+GG (HR = 3.28, 95% CI: 0.92-11.72, P = .001, I = 85.9%) were not associated with the OS of cancer patients. However, interestingly, the HR was greater for patients with the AA genotype than for those with the GG genotype, suggesting an association between TNF-α-308G>A polymorphism and OS among cancer patients (AA/GG, HR = 2.16, 95% CI: 1.36-3.43, P = .281, I = 21.5%).
CONCLUSION: TNF-α-308G>A polymorphism affects the OS of cancer patients and is a potential therapeutic target for cancer.

Luo MX, Long BB, Li F, et al.
Roles of Cyclooxygenase-2 gene -765G > C (rs20417) and -1195G > A (rs689466) polymorphisms in gastric cancer: A systematic review and meta-analysis.
Gene. 2019; 685:125-135 [PubMed] Related Publications
BACKGROUND: The roles of cyclooxygenase-2 (COX2) -765G > C (rs20417) and -1195G > A (rs689466) polymorphisms in gastric cancer were intensively analyzed, but the results of these studies were inconsistent. We conducted a meta-analysis and trial sequential analysis to elucidate the associations between these two COX2 polymorphisms and gastric cancer risk.
METHODS: Eligible studies were searched in PubMed, Embase, Cochrane library databases, China National Knowledge Infrastructure, Vip, and Wanfang databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the genetic correlation between COX2 polymorphisms and gastric cancer susceptibility in five genetic models. Trial sequential analysis (TSA) was conducted to estimate whether the evidence of the results is sufficient. Furthermore, their interactions with Helicobacter pylori (H. pylori) or smoking in gastric cancer were also assessed using a case-only method.
RESULTS: The COX2 gene -765G > C polymorphism showed no significant association with gastric cancer susceptibility under all the five genetic models (take the allelic model for example: OR = 1.41, 95% CI: 0.95-2.09) in total analysis, and the stratification analysis by ethnicity indicated a similar association in Caucasian group under four genetic models (allelic model, dominant model, homozygous model, and heterozygous model). But in the subgroup of the Asian population, the -765G > C polymorphism was significantly associated with gastric cancer risk under the same contrast. The COX2 -1195G > A polymorphism showed significant correlation with gastric cancer susceptibility in total analysis, and stratification analysis by ethnicity also revealed a similar association in both Asian and Caucasian groups under the same contrast. Moreover, TSA confirmed such associations. Both H. pylori infection and cigarette smoking interacted with -765 C allele in gastric cancer (OR = 3.79, 95% CI: 1.15-12.43 and OR = 2.48, 95% CI: 1.38-4.48, respectively), but not in -1195 A allele (OR = 1.96, 95% CI: 0.62-6.21, and OR = 1.24, 95% CI: 0.93-1.64, respectively).
CONCLUSIONS: COX2 -765G > C polymorphism may serve as a genetic biomarker of gastric cancer in Asians, but not in Caucasians. COX2 -1195G > A polymorphism may serve as a genetic biomarker of gastric cancer in both Asians and Caucasians. The -765G > C, rather than -1195G > A polymorphism interacted with H. pylori infection or cigarette smoking to increase gastric cancer risk.

Li Y, Liu Y, Xu H, et al.
Heterozygous deletion of chromosome 17p renders prostate cancer vulnerable to inhibition of RNA polymerase II.
Nat Commun. 2018; 9(1):4394 [PubMed] Free Access to Full Article Related Publications
Heterozygous deletion of chromosome 17p (17p) is one of the most frequent genomic events in human cancers. Beyond the tumor suppressor TP53, the POLR2A gene encoding the catalytic subunit of RNA polymerase II (RNAP2) is also included in a ~20-megabase deletion region of 17p in 63% of metastatic castration-resistant prostate cancer (CRPC). Using a focused CRISPR-Cas9 screen, we discovered that heterozygous loss of 17p confers a selective dependence of CRPC cells on the ubiquitin E3 ligase Ring-Box 1 (RBX1). RBX1 activates POLR2A by the K63-linked ubiquitination and thus elevates the RNAP2-mediated mRNA synthesis. Combined inhibition of RNAP2 and RBX1 profoundly suppress the growth of CRPC in a synergistic manner, which potentiates the therapeutic effectivity of the RNAP2 inhibitor, α-amanitin-based antibody drug conjugate (ADC). Given the limited therapeutic options for CRPC, our findings identify RBX1 as a potentially therapeutic target for treating human CRPC harboring heterozygous deletion of 17p.

Zhou L, Ma X, Yue J, et al.
The diagnostic effect of serum miR-139-5p as an indicator in osteosarcoma.
Cancer Biomark. 2018; 23(4):561-567 [PubMed] Related Publications
BACKGROUND: The microRNA, miR-139-5p, plays an important role in the initiation and progression of various tumor types including osteosarcoma (OS).
OBJECTIVE: This study aimed to detect the serum miR-139-5p expression in OS and analyze its association with clinical variables.
METHODS: Blood samples were taken from 98 OS patients and 50 healthy individuals, and serum miR-139-5p levels were measured by quantitative reverse transcription-polymerase chain reaction.
RESULTS: We found the expression of serum miR-139-5p in OS patients was significantly lower than that in healthy individuals, and miR-139-5p levels were dramatically decreased in patients with distant metastasis or in higher clinical stage. Receiver-operating characteristic (ROC) analysis revealed that serum miR-139-5p could well discriminate OS patients from healthy controls with a high sensitivity and specificity. Moreover, low serum miR-139-5p expression was strongly associated with distant metastasis, tumor stage and shorter overall survival. Both univariate and multivariate analyses showed that serum miR-139-5p level could serve as an independent prognostic marker for OS.
CONCLUSIONS: Taken together, data from this study demonstrates that serum miR-139-5p could be used as a tumor biomarker for OS diagnosis and prognosis.

Zhang S, Li P, Zhao L, Xu L
LINC00210 as a miR-328-5p sponge promotes nasopharyngeal carcinoma tumorigenesis by activating NOTCH3 pathway.
Biosci Rep. 2018; 38(6) [PubMed] Free Access to Full Article Related Publications
As a kind of essential regulators, long noncoding RNAs (lncRNAs) have attracted a lot of attention in recent years. Nevertheless, the function of lncRNA in nasopharyngeal carcinoma (NPC) remains poorly understood. In the present study, we explained the role and mechanism of LINC00210 in NPC progression. We found that LINC00210 expression was up-regulated in NPC samples. Besides, its overexpression was positively correlated with NPC metastasis while predicting poor prognosis. Based on functional experiments, we revealed that LINC00210 contributed to NPC cell proliferation and invasion

Xu B, Zhu Y, Tang Y, et al.
Rs4938723 Polymorphism Is Associated with Susceptibility to Hepatocellular Carcinoma Risk and Is a Protective Factor in Leukemia, Colorectal, and Esophageal Cancer.
Med Sci Monit. 2018; 24:7057-7071 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Growing evidence indicates that a non-coding RNA named miR-34b/c plays crucial roles in carcinogenesis, and its common polymorphism, pri-miR-34b/c rs4938723, also participates in this process and is associated with cancer susceptibility. However, this association was previously undefined and ambiguous. Therefore, we carried out an updated analysis to evaluate this relationship between rs4938723 polymorphism and cancer susceptibility. MATERIAL AND METHODS PubMed, EMbase, Web of Science and Chinese language (WanFang, CNKI and VIP) databases were searched for relevant studies until Sep 10, 2018. Odds ratios and 95% confidence interval were applied to assess this relationship. RESULTS Thirty case-control studies were retrieved. No positive association was found in either the overall study population or in the subgroups, based on ethnicity, source of group, sex, smoking, and drinking status. The main results were observed in the stratified analysis subgroups in cancer type subgroup: rs4938723 polymorphism may be a protective factor in leukemia, colorectal cancer, and esophageal cancer; however, C-allele was a risk factor in carriers for hepatocellular carcinoma. Last but not the least, poor positive results were discovered in the age subgroup. CONCLUSIONS Current meta-analysis suggested that rs4938723 polymorphism was potentially associated with hepatocellular carcinoma risk, but this polymorphism had a decreased association for susceptibility to esophageal cancer, leukemia, and colorectal cancer. Furthermore, studies with larger sample sizes and including gene-gene or gene-environment interactions should be carried out to elucidate the role of rs4938723 polymorphism in cancer risk.

Zhao CC, Chen J, Niu RF, et al.
Increased resistin suggests poor prognosis and promotes development of lung adenocarcinoma.
Oncol Rep. 2018; 40(6):3392-3404 [PubMed] Free Access to Full Article Related Publications
Resistin is considered to be a risk factor for several types of cancer, but its functions are controversial and not well studied in lung cancer. The present study is aimed to investigate the expression of resistin in lung adenocarcinoma tissues, in order to evaluate its association with the clinicopathological characteristics of cancer patients and to investigate the effects of resistin in lung adenocarcinoma cells. A total of 70 pairs of lung adenocarcinoma tissues and normal tissues were collected and immunohistochemistry was performed to examine resistin expression. Resistin overexpressed cells were established by plasmid transfection in A549 or H1975 cells. Alterations in cell proliferation, apoptosis, migration and invasion were analyzed in vitro. A nude mouse tumorigenicity assay was used to test the effect of resistin in vivo. High expression of resistin was predominantly observed in lung adenocarcinoma tissues but not in adjacent normal lung tissues. Resistin expression was significantly associated with increased tumor size, clinical stage as well as lymph node metastasis while negatively associated with progression-free survival (PFS) and overall survival (OS). Expression of resistin was an independent risk factor for PFS and OS. Overexpression of resistin promoted significant proliferation, migration and invasion, while also inhibited apoptosis in vitro. Resistin also promoted tumor formation in nude mice. The potential molecular mechanism was also investigated by in vitro experiments. In conclusion, the present study revealed that a high level of resistin expression in lung adenocarcinoma tissues is associated with poor clinicopathological status and survival. Resistin, which promotes the development of lung adenocarcinoma in vitro and in vivo may be a novel target for lung adenocarcinoma.

Li S, Han X, Lyu N, et al.
Mechanism and prognostic value of indoleamine 2,3-dioxygenase 1 expressed in hepatocellular carcinoma.
Cancer Sci. 2018; 109(12):3726-3736 [PubMed] Free Access to Full Article Related Publications
Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-metabolizing enzyme that is widely distributed in normal or malignant tissues and contributes to immunologic tolerance and immune escape. However, in hepatocellular carcinoma (HCC), the characteristics and mechanism of IDO1 expression have not been well defined. In this study, IDO1 expression in tumor cells (T-IDO1) was frequently detected (109/112) by immunohistochemistry in formalin-fixed paraffin-embedded specimens from HCC patients, and the expression patterns were mostly focal (102/109). Expression of T-IDO1 was significantly associated with the infiltration of CD8+ T cells (P = .043), as well as younger age (<50 years old, P = .02). It was also found that IDO1 had diffuse expression in inflammatory cells in all specimens, which were defined as antigen-presenting cells. Significant correlations among IDO1, IFNG, and CD8A transcriptional levels were observed in freshly resected HCC specimens; moreover, no constitutive IDO1 expression was detected in HCC cell lines until stimulated by interferon-γ through the JAK2-STAT1 signaling pathway, but not type I interferon. Survival analyses showed that increased T-IDO1 and CD8+ T cell infiltration were significantly associated with superior overall survival (OS) (T-IDO1, P = .003; CD8+ T cells, P = .004), and T-IDO1 expression is an independent prognosis factor in both OS and disease-free survival (OS, P = .007; disease-free survival, P = .044). These findings indicated that T-IDO1 expression in HCC is common and is dominantly driven by the host antitumor immune response, which is a favorable prognostic factor in HCC.

Yuan CW, Wang ZC, Liu K, Liu DJ
Incomplete radiofrequency ablation promotes the development of CD133
Hepatobiliary Pancreat Dis Int. 2018; 17(5):416-422 [PubMed] Related Publications
BACKGROUND: Cancer stem cells (CSCs) accelerate the growth of hepatocellular carcinoma (HCC) residual after incomplete radiofrequency ablation (In-RFA). The present study aimed to detect the effects of In-RFA on stemness transcription factors (STFs) expression which are important for the production and function of CSCs, and to find which STFs promote HCC stemness after In-RFA.
METHODS: HepG2 cells were used for in vitro and in vivo studies. Flow cytometry and sphere-formation assays were used to detect the level and function of CD133
RESULTS: In-RFA was identified to induce CD133
CONCLUSION: In-RFA-induced SOX9 stimulates CD133

Dou C, Zhou Z, Xu Q, et al.
Hypoxia-induced TUFT1 promotes the growth and metastasis of hepatocellular carcinoma by activating the Ca
Oncogene. 2019; 38(8):1239-1255 [PubMed] Related Publications
Tuftelin1 (TUFT1), an acidic protein constituent of developing and mineralizing tooth tissues, is regulated by hypoxia and the Hedgehog signaling pathway. We investigated the role of TUFT1 in hepatocellular carcinoma (HCC). qRT-PCR, immunohistochemistry and western blot were employed to evaluate TUFT1 level in HCC. MTT, BrdU, 3D culture and Transwell assays were used to assess cell viability, proliferation, in vitro growth, migration, and invasion. Subcutaneous and tail vein injection models were established to investigate in vivo growth and metastasis. Chromatin immunoprecipitation was performed to assess binding of hypoxia-inducible factor 1α (HIF-1α) to TUFT1 promoter. A microRNA array was used to identify hypoxia-related microRNAs. TUFT1 was elevated in HCC, and correlated with unfavorable clinicopathologic characteristics and poor survival. TUFT1 promoted HCC cell growth, metastasis and epithelial-mesenchymal transition in vitro and in vivo via activation of Ca

Liu H, Liu Z, Liu XW, et al.
A similar effect of P16 hydroxymethylation and true-methylation on the prediction of malignant transformation of oral epithelial dysplasia: observation from a prospective study.
BMC Cancer. 2018; 18(1):918 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Total P16 methylation (P16M), including P16 hydroxymethylation (P16H) and true-P16M, correlates with malignant transformation of oral epithelial dysplasia (OED). Both true-P16M and P16H are early events in carcinogenesis. The aim of this study is to prospectively determine if discrimination of true-P16M from P16H is necessary for prediction of cancer development from OEDs.
METHODS: Patients (n = 265) with mild or moderate OED were recruited into the double blind two-center cohort. Total-P16M and P16H were analyzed using the 115-bp MethyLight, TET-assisted bisulfite (TAB) methylation-specific PCR (MSP), and TAB-sequencing. Total-P16M-positive and P16H-negative samples were defined as true-P16M-positive. Progression of OEDs was monitored for a minimum 24 months follow-up period.
RESULTS: P16H was detected in 23 of 73 (31.5%) total-P16M-positive OEDs. Follow-up information was obtained from 247 patients with an ultimate compliance rate of 93.2%. OED-derived squamous cell carcinomas were observed in 13.0% (32/247) patients during follow-up (median, 41.0 months). The cancer progression rate for total-P16M-positive patients was significantly increased when compared to total-P16M-negative patients [23.3% vs 8.6%; adjusted odds ratio = 2.67 (95% CI: 1.19-5.99)]. However, the cancer progression rates were similar between P16H- and true-P16M-positive OEDs [26.1% (6/23) vs 22.0% (11/50); odds ratio = 0.80 (95% CI: 0.22-2.92)]. The cancer-free survival was also similar for these patients.
CONCLUSION: P16H and true-P16M are similar biomarkers for determining malignant potential of OEDs. Discrimination of P16H from true-P16M, at least in OED, may be not necessary in clinical applications.
TRIAL REGISTRATION: This study is registered prospectively in the U.S. National Institutes of Health Clinical Trials Protocol Registration System (trial number NCT02967120, available at ).

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