miR-30a-5p/PHTF2 axis regulates the tumorigenesis and metastasis of lung adenocarcinoma

Background:Lung adenocarcinoma is a very pervasive histological form of lung cancers,and inhibiting metastasis is crucial for effective treatment.In this investigation,we explored the functional interaction of miR-30a-5p and the putative transcription factor 2 of the homeodomain(PHTF2)in dictating the aggressiveness and metastasis of lung adenocarcinoma.Method:We collected clinical samples to evaluate the expression patterns of miR-30a-5p and PHTF2 in lung adenocarcinoma along with normal tissues.Cellular experiments including cell count kit(CCK)-8 growth assay,apoptosis analysis,migration and invasion examinations were performed to assess the aggressiveness of lung adenocarcinoma cells.Furthermore,we examined tumorigenesis and metastasis in a nude mouse model.Results:MiR-30a-5p exhibited downregulation pattern in lung adenocarcinoma samples.Transfection of miR-30a-5p mimic in lung adenocarcinoma cells resulted in the suppression of malignant characteristics.Notably,the administration of miR-30a-5p mimic also curbed tumorigenesis and metastasis of lung adenocarcinoma cells in animal model.Moreover,PHTF2 was found to be a molecular target of miR-30a-5p.Upregulating PHTF2 counteracted the tumor-suppressive effect of the miR-30a-5p mimic.Conclusion:miR-30a-5p functions as a tumor-suppressive molecule while PHTF2 acts as an oncogenic factor in the development and metastasis of lung adenocarcinoma.Therefore,targeting miR-30a-5p and PHTF2 could be developed into a promising therapeutic approach for inhibiting metastasis in lung adenocarcinoma.

A survey and evaluation of population-based screening for gastric cancer

Screening and early diagnosis of gastric cancer play important roles in reducing the mortality of gastric cancer. A vast amount of study data on gastric cancer screening and early diagnosis has been accumulated in and out of China in the past decades. The practice of gastric cancer screening has also been efficiently carried out in different countries and regions. However, no widely accepted principle of population screening for gastric cancer has been developed yet. Screening for gastric cancer requires extensive exploration both theoretically and practically. This article focuses on the method and program of gastric cancer screening based on population. Moreover, the current situation of gastric cancer screening and its evaluation are evaluated.

Association of twelve polymorphisms in three onco-lncRNA genes with hepatocellular cancer risk and prognosis:A case-control study

AIM To evaluate the association of 12 tag single nucleotide polymorphisms(tag SNPs) in three onco-long non-coding RNA(lnc RNA) genes(HOTTIP,CCAT2,MALAT1) with the risk and prognosis of hepatocellular cancer(HCC). METHODS Twelve tag SNPs covering the three onco-lnc RNAs were genotyped by the KASP method in a total of 1338 samples,including 521 HCC patients and frequencymatched 817 controls. The samples were obtained from an unrelated Chinese population at the First Hospital ofChina Medical University from 2012-2015. The expression quantitative trait loci(e QTL) analyses were conducted to explore further the potential function of the promising SNPs. RESULTS Three SNPs in HOTTIP,one promoter SNP in MALAT1,and one haplotype of HOTTIP were associated with HCC risk. The HOTTIP rs17501292,rs2067087,and rs17427960 SNPs were increased to 1.55-,1.20-,and 1.18-fold HCC risk under allelic models(P = 0.012,0.017 and 0.049,respectively). MALAT1 rs4102217 SNP was increased to a 1.32-fold HCC risk under dominant models(P = 0.028). In addition,the two-way interaction of HOTTIP rs17501292-MALAT1 rs619586 polymorphisms showed a decreased effect on HCC risk(P interaction = 0.028,OR = 0.30) and epistasis with each other. HOTTIP rs3807598 variant genotype showed significantly longer survival time in HBV negative subgroup(P = 0.049,HR = 0.12),and MALAT1 rs591291 showed significantly better prognosis in female and HBV negative subgroups(P = 0.022,HR = 0.37; P = 0.042,HR = 0.25,respectively). In the study,no significant effect was observed in e QTL analysis. CONCLUSION Specific lnc RNA(HOTTIP and MALAT1) SNPs have potential to be biomarkers for HCC risk and prognosis.

Protein expression trends of DNMT1 in gastrointestinal diseases:From benign to precancerous lesions to cancer

BACKGROUND In recent years,the incidence of gastrointestinal(GI)cancer in China has increased annually.Early detection and appropriate therapy are considered to be the key to treat GI cancer.DNMT1 takes an active part in the advancement of GI cancer,which will change as the disease progresses.But its expression characteristics in the dynamic variations of GI carcinogenesis are still unclear.AIM To investigate the expression characteristics of DNMT1 in different GI diseases.METHODS We detected the expression of DNMT1 in 650 cases of different GI diseases by immunohistochemistry,including 90 cases of chronic superficial gastritis(CSG),72 cases of atrophic gastritis with intestinal metaplasia(AG/GIM),54 cases of low-grade intraepithelial neoplasia(GLIN),66 cases of high-grade intraepithelial neoplasia(GHIN),71 cases of early gastric cancer(EGC),90 cases of normal intestinal mucosa(NIM),54 cases of intestinal low-grade intraepithelial neoplasia(ILIN),71 cases of intestinal high-grade intraepithelial neoplasia(IHIN),and 82 cases of early colorectal cancer(ECRC).RESULTS In the CSG group,all cases showed weakly positive or negative expression of DNMT1.However,in other four groups(AG/GIM,GLIN,GHIN,and EGC),the positive expression rate gradually increased with the severity of the diseases;the negative or weakly positive cases accounted for 55.56%(40/72),38.89%(21/54),1.52%(1/66),and 1.41%(1/71),respectively.Besides,the moderately positive cases were 44.44%(32/72),57.41%(31/54),80.30%(53/66),and 43.66%(31/71),respectively.The strongly positive cases only existed in the GLIN(3.70%,2/54),GHIN(18.18%,12/66),and EGC(54.93%,39/71)groups.The differences between any two groups were statistically significant(P<0.05).Similarly,in the NIM group,cases with weakly positive expression of DNMT1 were predominant(91.11%,82/90),and the rest were moderately positive cases(8.89%,8/90).In the ILIN,IHIN,and ECRC groups,the rates of cases with weak or negative expression of DNMT1 were 46.30%(25/54),12.68%(9/71),and 4.88%(4/82),respectively;with moderately positive expression were 53.70%(29/54),71.83%(51/71),and 34.15%(28/82),respectively;and with strongly positive expression were 0.00%(0/54),15.49%(11/71),and 60.98%(50/82),respectively.The differences between any two groups were also statistically significant(P<0.05).CONCLUSION The overexpression of DNMT1 protein could effectively predict early GI cancers and severe precancerous lesions,which may have potential clinical application value.

Impact of SNP-SNP interactions of DNA repair gene ERCC5 and metabolic gene GSTP1 on gastric cancer/atrophic gastritis risk in a Chinese population

AIM To investigate the interactions of the DNA repair gene excision repair cross complementing group 5(ERCC5) and the metabolic gene glutathione S-transferase pi 1(GSTP1) and their effects on atrophic gastritis(AG) and gastric cancer(GC) risk.METHODS Seven ERCC5 single nucleotide polymorphisms(SNPs)(rs1047768, rs2094258, rs2228959, rs4150291, rs4150383, rs751402, and rs873601) and GSTP1 SNP rs1695 were detected using the Sequenom MassA RRAY platform in 450 GC patients, 634 AG cases, and 621 healthy control subjects in a Chinese population.RESULTS Two pairwise combinations(ERCC5 rs2094258 and rs873601 with GSTP1 rs1695) influenced AG risk(P_(interaction) = 0.008 and 0.043, respectively), and the ERCC5 rs2094258-GSTP1 rs1695 SNP pair demonstrated an antagonistic effect, while ERCC5 rs873601-GSTP1 rs1695 showed a synergistic effect on AG risk OR = 0.51 and 1.79, respectively). No pairwise combinations were observed in relation to GC risk. There were no cumulative effects among the pairwise interactions(ERCC5 rs2094258 and rs873601 with GSTP1 rs1695) on AG susceptibility(P_(trend) > 0.05). When the modification effect of Helicobacter pylori(H. pylori) infection was evaluated, the cumulative effect of one of the aforementioned pairwise interactions(ERCC5 rs873601-GSTP1 rs1695) was associated with an increased AG risk in the case of negative H. pylori status(P_(trend)= 0.043).CONCLUSION There is a multifarious interaction between the DNA repair gene ERCC5 SNPs(rs2094258 and rs873601) and the metabolic gene GSTP1 rs1695, which may form the basis for various inter-individual susceptibilities to AG.

Association of Helicobacter pylori babA2 with peptic ulcer disease and gastric cancer

AIM: To investigate the association between babA2 gene and peptic ulcer disease (PUD) and gastric cancer (GC) in Helicobacter pylori -infected populations. METHODS: We evaluated the relationship between babA2 and clinical outcomes (PUD and GC) using a meta-analysis. A literature search was performed using the PubMed and Web of Science databases for relevant case-control studies that met the defined inclusion criteria. The ORs and 95%CIs were calculated to estimate the association between babA2 genotype and clinical outcomes. A fixed-effect or random-effect model was performed depending on the absence or presence of significant heterogeneity. RESULTS: A total of 25 articles with 38 studies met the inclusion criteria and were finally included in this metaanalysis. The results showed that the babA2 genotype was significantly associated with an increased risk of PUD (OR = 2.069, 95%CI: 1.530-2.794, P < 0.001) and especially in the subgroup of duodenal ulcer (OR = 1.588, 95%CI: 1.141-2.209, P = 0.006). Moreover, a significant association between babA2 gene and PUD and duodenal ulcer (OR = 2.739, 95%CI: 1.860-4.032, P < 0.001; OR = 2.239, 95%CI: 1.468-3.415, P < 0.001, respectively) was observed in western countries but not in Asian countries. CONCLUSION: We demonstrated that the presence of babA2 may be associated with increased risks for PUD, especially duodenal ulcer, in western countries.

PGC-MG7 combination could be used as a follow-up panel for monitoring dynamical progression of gastric precancerous diseases

Objective: The aim of this study was to investigate the value of the combined expression of the gastric mucosal differentiation protein pepsinogen C(PGC) and gastric cancer(GC)-associated antigen MG7 for the diagnosis of GC and prediction of the development from precancerous conditions to GC.Methods: The gastric mucosal biopsies of 285 subjects enrolled from a region with a high incidence of GC were obtained and histopathologically examined. Subjects testing negative for GC(n=208) were followed up from 1998 to 2015. The levels of PGC and MG7 in the biopsies were determined by immunohistochemistry.Results: PGC was positive in 91.4% of the non-atrophic gastritis, 26.5% of the atrophic gastritis, and 0% of the GC. MG7 was positive in 15.0% of the non-atrophic gastritis, 82.4% of the atrophic gastritis, and 94.8% of the GC. The non-atrophic gastritis group was predominantly "PGC+MG7-". The atrophic gastritis and GC groups were predominantly "PGC-MG7+". The rate of GC in subjects with "PGC-MG7+" staining was 113.4-fold higher [95% confidence interval(95% CI): 15.3-869.4, P<0.001] than that in subjects with other staining patterns.The sensitivity and specificity of the "PGC-MG7+" pattern were 92.2% and 78.8% for the detection of GC and77.2% and 97.9% for GC and precancerous disease, respectively. In the follow-up cohort of non-GC subjects, the risk of developing GC was higher in those with the "PGC-MG7+" staining pattern.Conclusions: Our data suggest that the "PGC-MG7+" pattern can be employed as a useful follow-up panel for detecting individuals with a high risk of GC, and the dynamic assessment of the follow-up panel needs multi-centre large-scale validation in the future.

Nucleotide excision repair pathway gene polymorphisms are associated with risk and prognosis of colorectal cancer

BACKGROUND Single nucleotide polymorphisms(SNPs)are universally present in nucleotide excision repair(NER)pathway genes,which could make impacts on colorectal carcinogenesis and prognosis.AIM To explore the association of all tagSNPs in NER pathway genes with colorectal cancer(CRC)risk and prognosis in a northern Chinese population by a two-stage case-control design composed of a discovery and validation stage.METHODS Genotyping for NER SNPs was performed using kompetitive allele specific PCR.In the discovery stage,39 tagSNPs in eight genes were genotyped in 368 subjects,including 184 CRC cases and 184 individual-matched controls.In the validation stage,13 SNPs in six genes were analyzed in a total of 1712 subjects,including 854 CRC cases and 858 CRC-free controls.RESULTS Two SNPs(XPA rs10817938 and XPC rs2607775)were associated with an increased CRC risk in overall and stratification analyses.Significant cumulative and interaction effects were also demonstrated in the studied SNPs on CRC risk.Another two SNPs(ERCC2 rs1052555 and ERCC5 rs2228959)were newly found to be associated with a poor overall survival of CRC patients.CONCLUSION Our findings suggest novel SNPs in NER pathway genes that can be predictive for CRC risk and prognosis in a large-scale Chinese population.The present study has referential values for the identification of all-round NER-based genetic biomarkers in predicting the susceptibility and clinical outcome of CRC.

Sun-burn induced upper limb lymphedema 11 years following breast cancer surgery: A case report

BACKGROUND Upper arm lymphedema is a common complication one year after breast cancer surgery,which profoundly impacts patients'quality of life.CASE SUMMARY We reported a case of lymphedema induced by prolonged sun exposure 11 years after breast cancer surgery.CONCLUSION Breast screening,patient education and follow-up after hospital discharge could help to prevent upper-arm lymphedema.

Effect of intra-operative chemotherapy with 5-fluorouracil and leucovorin on the survival of patients with colorectal cancer after radical surgery: a retrospective cohort study

Background:The effect of intra-operative chemotherapy(IOC)on the long-term survival of patients with colorectal cancer(CRC)remains unclear.In this study,we evaluated the independent effect of intra-operative infusion of 5-fluorouracil in combination with calcium folinate on the survival of CRC patients following radical resection.Methods:1820 patients were recruited,and 1263 received IOC and 557 did not.Clinical and demographic data were collected,including overall survival(OS),clinicopathological features,and treatment strategies.Risk factors for IOC-related deaths were identified using multivariate Cox proportional hazards models.A regression model was developed to analyze the independent effects of IOC.Results:Proportional hazard regression analysis showed that IOC(hazard ratio[HR]=0.53,95%confidence intervals[CI][0.43,0.65],P<0.001)was a protective factor for the survival of patients.The mean overall survival time in IOC group was 82.50(95%CI[80.52,84.49])months,and 71.21(95%CI[67.92,74.50])months in non-IOC group.The OS in IOC-treated patients were significantly higher than non-IOC-treated patients(P<0.001,log-rank test).Further analysis revealed that IOC decreased the risk of death in patients with CRC in a non-adjusted model(HR=0.53,95%CI[0.43,0.65],P<0.001),model 2(adjusted for age and gender,HR=0.52,95%CI[0.43,0.64],P<0.001),and model 3(adjusted for all factors,95%CI 0.71[0.55,0.90],P=0.006).The subgroup analysis showed that the HR for the effect of IOC on survival was lower in patients with stage II(HR=0.46,95%CI[0.31,0.67])or III disease(HR=0.59,95%CI[0.45,0.76]),regardless of pre-operative radiotherapy(HR=0.55,95%CI[0.45,0.68])or pre-operative chemotherapy(HR=0.54,95%CI[0.44,0.66]).Conclusions:IOC is an independent factor that influences the survival of CRC patients.It improved the OS of patients with stages II and III CRC after radical surgery.Trial registration:chictr.org.cn,ChiCTR 2100043775.

Tetrandrine citrate eliminates imatinib-resistant chronic myeloid leukemia cells in vitro and in vivo by inhibiting Bcr-Abl/β-catenin axis

Objective:To evaluate the effects of tetrandrine citrate, a novel tetrandrine salt with high water solubility, on the growth of imatinib (IM)-resistant chronic myeloid leukemia (CML) in vitro and in vivo, and reveal action molecular mechanisms. Methods:Cell viability in vitro was measured using methyl thiazolyl tetrazolium (MTT) assay. CML cell growth in vivo was assessed using a xenograft model in nude mice. Bcr-Abl and β-catenin protein levels were determined using Western blotting. Bcr-Abl messenger RNA (mRNA) was measured by reverse transcription polymerase chain reaction (RT-PCR). Flow cytometry (FCM) was used to determine cell cycle status. Results:Tetrandrine citrate inhibited the growth of IM-resistant K562 cells, primary leukemia cells, and primitive CD34 + leukemia cells, and their inhibition concentration that inhibited 50% of target cells (IC 50 ) ranged from 1.20 to 2.97 μg/ml. In contrast, tetrandrine citrate did not affect normal blood cells under the same conditions, and IC 50 values were about 10.12-13.11 μg/ml. Oral administration of tetrandrine citrate caused complete regression of IM-resistant K562 xeno-grafts in nude mice without overt toxicity. Western blot results revealed that treatment of IM-resistant K562 cells with tetrandrine citrate resulted in a significant decrease of both p210 Bcr-Abl and β-catenin proteins, but IM did not affect the Bcr-Abl protein levels. Proteasome inhibitor, MG132, did not prevent tetrandrine-mediated decrease of the p210 Bcr-Abl protein. RT-PCR results showed that tetrandrine treatment caused a decrease of Bcr-Abl mRNA. FCM analysis indicated that tetrandrine induced gap 1 (G 1 ) arrest in CML cells. Conclusions:Tetrandrine citrate is a novel orally active tetrandrine salt with potent anti-tumor activity against IM-resistant K562 cells and CML cells. Tetrandrine citrate-induced growth inhibition of leukemia cells may be involved in the depletion of p210 Bcr-Abl mRNA and β-catenin protein.

驱动蛋白KIF4A通过调节肺耐药相关蛋白LRP的胞内运输参与肿瘤耐药（英文）

目的:探讨驱动蛋白KIF4A调节肺耐药相关蛋白LRP在细胞内分布的作用机制,及其在肿瘤耐药过程中的作用。创新点:首次发现驱动蛋白KIF4A的C端区与肺耐药相关蛋白LRP的N端区结合,且KIF4A调节LRP在胞内分布依赖KIF4A的N端马达结构域。方法:应用免疫共沉淀和免疫荧光技术检测KIF4A与LRP的结合。根据KIF4A及LRP蛋白结构,构建绿色荧光蛋白(GFP)融合KIF4A截短突变质粒及Flag融合LRP截短突变质粒,免疫沉淀分析KIF4A与LRP相互作用区域。通过RNA干涉(RNAi)内源KIF4A,外源转入KIF4A截短突变体质粒,检测LRP在胞内分布。结论:本实验中免疫沉淀及免疫荧光结果显示,KIF4A与LRP结合,且在微管上有共定位(图1)。截短突变体免疫沉淀实验结果表明,KIF4A的C端尾部结构域与LRP的N端区结合(图2),RNAi敲降内源KIF4A表达导致LRP聚集在细胞核周围(图3),外源表达全长KIF4A可恢复LRP在胞内弥散状定位,但外源表达KIF4A的C端或N端截短突变无法恢复LRP的胞内定位,仍聚集在核周区域(图4)。综上所述,驱动蛋白KIF4A可与LRP结合,并调节LRP在胞内定位,KIF4A的C端尾部结构域与LRP结合,N端马达结构域促进LRP在胞内运输,二者缺一不可。