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Cancer cells typically experience higher oxidative stress than normal cells, such that elevating pro-oxidant levels can trigger cancer cell death. Although pre-exposure to mild oxidative agents will sensitize cancer cells to radiation, this pre-exposure may also activate the adaptive stress defense system in normal cells. Ascorbic acid is a prototype redox modulator that when infused intravenously appears to kill cancers without injury to normal tissues; however, the mechanisms involved remain elusive. In this study, we show how ascorbic acid kills cancer cells and sensitizes prostate cancer to radiation therapy while also conferring protection upon normal prostate epithelial cells against radiation-induced injury. We found that the NF-κB transcription factor RelB is a pivotal determinant in the differential radiosensitization effects of ascorbic acid in prostate cancer cells and normal prostate epithelial cells. Mechanistically, high reactive oxygen species concentrations suppress RelB in cancer cells. RelB suppression decreases expression of the sirtuin SIRT3 and the powerful antioxidant MnSOD, which in turn increases oxidative and metabolic stresses in prostate cancer cells. In contrast, ascorbic acid enhances RelB expression in normal cells, improving antioxidant and metabolic defenses against radiation injury. In addition to showing how RelB mediates the differential effects of ascorbic acid on cancer and normal tissue radiosensitivities, our work also provides a proof of concept for the existence of redox modulators that can improve the efficacy of radiotherapy while protecting against normal tissue injury in cancer settings. Cancer Res; 77(6); 1345–56. ©2017 AACR.

After treatment with AA, the expression of RelB, Bcl-xL, and Bax in PC3 and PZ cells was quantified by western blots by RT-PCR.

Legends for Supplemental Table S1 and Supplemental Figures S1-S3.

It has been established that 8-oxoguanine DNA glycosylase 1 (OGG1) is the main enzyme removing oxidized guanine under oxidative stress. However, increasing evidence has shown that OGG1 is not only a base excision repair protein but also a new transcriptional coactivator involved in oxidative stress-induced gene expression. Its downstream target genes and the underlying regulatory mechanisms still need to be discerned. Here, it was discovered that c-Myc is a downstream target of OGG1 under oxidative stress and that H4R3me2a is involved in this transcriptional regulation. The increased level of H4R3me2a induced by H2O2 is regulated by OGG1, which may directly interact with the specific arginine methyltransferase PRMT1 and promote the asymmetrical dimethylation of H4R3me1. H4R3me2a enrichment on the promoter of c-Myc can recruit YY1 and activate c-Myc transcription. Moreover, knocking down OGG1 or PRMT1 suppresses c-Myc transcription under oxidative stress by downregulating H4R3me2a formation. Furthermore, the overexpression of wild type (WT) H4R3 promotes c-Myc transcription, but the expression of mutant H4R3Q does not have this effect. Taken together, our data show that the 8-oxoG/OGG1/PRMT1/H4R3me2a/YY1 axis senses oxidative stress and promotes gene transcription.

Sorafenib has been approved for the treatment of certain cancers in clinic. However, the effects of sorafenib on gastric adenocarcinoma (GAC) were still limited. This study aimed to evaluate both in vitro and in vivo efficacy of sorafenib in combination with pterostilbene (PTE) on the treatment of GAC. Here, the morphological changes and cell viability were recorded in both N87 and MKN45 cells. The cell cycle profile and apoptosis were assessed by flow cytometry. Subcutaneous tumour xenografts were constructed in nude mice, and IHC staining of the dissected tumour tissues was conducted. Our results showed that PTE enhanced sorafenib's inhibitory effects on cell viability. The obvious down‐regulation of cyclin D1, Cdk‐2, Cdk‐4, Cdk‐6 and p62 and the up‐regulation of LC3II, caspase‐9, caspase‐3 and PARP cleavages were observed for the combination treatment with PTE and sorafenib than monotherapy. The combination treatment resulted in a higher level of cell cycle arrest at G1 phase and apoptosis than either drug. Besides, drug combination significantly enhanced the inhibition of tumour growth than sorafenib or PET alone in nude mice. The percentage of Ki‐67‐ and PCNA‐positive cells was distinctly reduced, and the apoptotic cells was obviously increased when compared with single drug therapy. Altogether, PET obviously enhanced sorafenib's antitumour effects against GAC through inhibiting cell proliferation, inducing autophagy and promoting apoptosis. The combination therapy with PET and sorafenib may serve as a novel therapeutic strategy for treating GAC and deserve further clinical trials.

Background IKBKB/IKKβ, as the core catalytic subunit of IκB kinase complex, participates in mediation of the classical NF-κB pathway, which has been linked to inflammation and tumorigenesis. Previous studies have shown that single nucleotide polymorphisms in IKBKB have been related to gastric cancer, but how they associate to the clinical outcome is not yet clear. In this study, we retrospectively investigated the associations between single nucleotide polymorphisms located in IKBKB and gastric cancer survival. Materials and Methods IKBKB rs2272736 was genotyped in 1210 patients with primary gastric cancer in a Han Chinese population, and the relationships between rs2272736 and overall survival were evaluated. We conducted Cox proportional hazards regression, which was performed to estimate the effects of single nucleotide polymorphisms on the overall survival of patients, adjusted for potential confounding variables. Results We found that patients with rs2272736 A allele in IKBKB had significantly prolonged overall survival time compared to those with the G allele (HR = 0.83, 95% CI = 0.68-1.00, P = 0.050). In addition, AA genotype was demonstrated to have reduced risk of death for gastric cancer compared with that associated with the GG/GA genotypes, which was more common in patients with cardiac carcinoma, well-differentiated and moderately differentiated tumors, TNM Ⅰ/Ⅱ stages and intestinal type. Conclusion Our findings have shown that single nucleotide polymorphism rs2272736 in IKBKB may be a promising prognostic biomarker which should promote personalized treatment.

Background: The effect of Helicobacter pylori (H. pylori) status on survival for gastric cancer remains unclear. We aimed to elucidate the molecular heterogeneity of tumour-infiltrating T cells in gastric cancer with different H. pylori infection status.Methods: We conducted a prognostic analysis of 488 gastric cancer patients and performed single-cell RNA sequencing (scRNA-seq) analysis on 18,717 T cells from 6 tumour samples with or without H. pylori infection. Analysis results were validated using histological assays and bulk transcriptomic datasets.Results: We confirmed that gastric cancer patients with H. pylori infection had a significantly longer survival time compared to patients with negative H. pylori status (HR=0.74, 95% CI=0.55-0.99, P= 0.045). After unsupervised re-clustering of T cells based on scRNA-seq data, we identified ten CD4+ and twelve CD8+ clusters. Among them, four clusters in CD8+ T cells appeared to exhibit distinct distributions with different H. pylori infection status. One subgroup marked by CXCL13, which contained mostly cells of H. pylori infection and expressed high levels of IFNG, GZMB and low level of PDCD1, was activated by TNFRSF1A-TNF interaction. The developed gene signature was significantly associated with improved patient survival in gastric cancer. The other subgroup specifically expressed immune suppression-related genes AREG and PTGER2, was almost exclusively populated with cells without H. pylori infection. High PTGER2 expression was significantly associated with worse prognosis with high CD8 expression.Conclusion: Our results shed light into the mechanisms underlying the target cell dependent T cell responses induced by H. pylori, which will provide assistance for precision treatment and prognosis.

Significance Here, we report that the long noncoding RNA lysosome cell death regulator ( LCDR ) mediates the survival of cancer cells, counteracting the effects of apoptosis triggered by lysosomal cell death pathways. Mechanistically, LCDR , as a cofactor for heterogenous nuclear ribonucleoprotein K (hnRNP K) to potentiate the stabilization of lysosomal membrane protein lysosomal-associated protein transmembrane 5 (LAPTM5), prevents lysosomal membrane permeabilization and promotes cancer cell survival. Clinically, LCDR , hnRNP K, and LAPTM5 are significantly up-regulated in lung adenocarcinoma (LUAD) patients. Targeting LCDR via nanoparticles-mediated RNA interference technology increases cell death in vitro and inhibits the growth of patient-derived xenografts of LUAD in vivo. Our study demonstrates that LCDR contributes to cancer pathology by regulating LCDR -mediated apoptosis.

Jian Yang,1,2,* Wei Zheng,3,* Zhi Xu,1,4 Jinfei Chen1,5,61Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, People’s Republic of China; 2Department of Oncology, The Affiliated Yixing Hospital of Jiangsu University, Yixing 214200, People’s Republic of China; 3Department of General Surgery, The Affiliated Yixing Hospital of Jiangsu University, Yixing 214200, People’s Republic of China; 4ICR Medical Affairs, ICON Plc, Shanghai 200003, People’s Republic of China; 5Cancer Center, TaiKang Xianlin Drum Tower Hospital, Nanjing University School of Medicine, Nanjing 210046, People’s Republic of China; 6Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 210006, People’s Republic of ChinaCorrespondence: Jinfei ChenDepartment of Oncology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, People’s Republic of ChinaTel +86 258 535 8120Fax +86 258 535 8120Email jinfeichen@sohu.com*These authors contributed equally to this workBackground: For patients with gastric cancer (GC), adjuvant chemotherapy is a standard therapy. However, the responses to the treatment are quite different. Mitogen-activated protein kinase (MAPK) pathway is a core pathway that modulates the efficacy of anticancer drugs. The purpose of our study was to investigate the clinical significance of one pivotal functional gene polymorphism in the MAPK pathway – MAP3K1 rs889312 – in patients with stage II GC to stage III GC.Methods: The genotypes of MAP3K1 rs889312 were analyzed in 591 GC patients enrolled in this study who had received radical gastrectomy. Among them, 204 patients accepted adjuvant chemotherapy based on platinum and fluorouracil (PF) regimens after an operation. Cox regression analysis, log-rank test and Kaplan–Meier method were used to explore the link between MAP3K1 rs889312 variant and overall survival (OS) of GC.Results: Compared with the AA genotype (mean OS of 68.12 months), MAP3K1 rs889312 AC/CC significantly reduced the mean OS of 56.83 months in patients who received adjuvant chemotherapy only. In addition, AC/CC genotype had a negative impact on OS of patients who received oxaliplatin-based therapy (HR, 8.253; 95% CI: 1.119–60.853, log-rank p=0.013). Stratification analysis showed that MAP3K1 rs889312 AC/CC significantly reduced OS of patients with tumors smaller than or equal to 5 cm in size (HR, 3.706; 95% CI: 1.329–10.335, p=0.012), poorly differentiated tumors (HR, 3.002; 95% CI: 1.076–8.377, p=0.036) and intestinal tumors (HR, 4.780; 95% CI: 1.138–20.073, p=0.033).Conclusion: Our findings suggested that MAP3K1 rs889312 single-nucleotide polymorphism may be considered as a biomarker for adjuvant chemotherapy reaction and can predict prognosis of GC patients who received PF-based therapy.Keywords: MAP3K1 rs889312, gastric cancer, biomarker, single-nucleotide polymorphism, adjuvant chemotherapy

BACKGROUND The aim of this study was to assess the ability of polyethylenimine (PEI) as an E1A plasmid vector to transfect hepatocellular carcinoma SMMC-7721 cells and to analyze the sensitization effect of E1A on various anti-tumor drugs. MATERIAL AND METHODS PEI-mediated recombinant plasmid psv-E1A with high expression of the E1A gene was introduced into hepatocellular carcinoma SMMC-7721 cells, and the effective transfection of E1A gene was determined by RT-PCR and Western blot analysis. The CCK8 method was used to detect the proliferation inhibition of docetaxel, epirubicin, gemcitabine, and 5-fluorouracil on SMMC-7721 cells before and after the transfection of the E1A gene. RESULTS RT-PCR and Western blot analysis showed that PEI could transfect plasmid psv-E1A with stable expression. After the transfection of E1A gene, the sensitivity of SMMC-7721 cells to docetaxel, epirubicin, gemcitabine, and 5-fluorouracil was increased (P

Background:The gene metastasis-associated in colon cancer-1 (MACC1) has been reported to be overexpressed in diverse human malignancies, and an increasing amount of evidence suggests that its overexpression is associated with the development and progression of many human tumors. However, the prognostic and clinicopathological value of MACC1 in gastric cancer remains inconclusive. Therefore, we conducted this meta-analysis to investigate the effect of positive MACC1 expression on clinicopathological features and survival outcomes in gastric cancer.Methods:Medline, Web of Science, and EMBASE databases were searched for relevant articles published up to 10 April 2018. The correlation of MACC1 expression levels with overall survival and clinicopathological features was analyzed.Results:In this meta-analysis, nine studies with a total of 2103 gastric cancer patients were included. Our results showed that high expression of MACC1 was significantly related to a poor overall survival. Moreover, our meta-analysis showed that MACC1 overexpression was significantly linked to distant metastasis and vascular invasion. There were no significant correlations between positive MACC1 expression and gender, localization, tumor-node-metastasis (TNM) stage, tumor extent (T stage) and lymph node involvement (N stage)Conclusions:MACC1 expression levels can serve as a novel prognostic factor in gastric cancer patients.

Advances in single-cell sequencing technology provide a unique approach to characterize the heterogeneity and distinctive functional states at single-cell resolution, leading to rapid accumulation of large-scale single-cell datasets. A big challenge undertaken by research community especially bench scientists is how to simplify the way of retrieving, processing and analyzing the huge number of datasets. Towards this end, we developed Cell-omics Data Coordinate Platform (CDCP), a platform that aims to share and integrate comprehensive single-cell datasets, and to provide a network analysis toolkit for personalized analysis. CDCP contains single-cell RNA-seq and ATAC-seq datasets of 474 572 cells from 6 459 samples in species covering humans, non-human primate models and other animals. It allows querying and visualization of interested datasets and the expression profile of distinct genes in different cell clusters and cell types. Besides, this platform provides an analysis pipeline for non-bioinformatician experimental scientists to address questions not focused by the submitters of the datasets. In summary, CDCP provides a user-friendly interface for researchers to explore, visualize, analyze, download and submit published single-cell datasets and it will be a valuable resource for investigators to explore the global transcriptome profiling at single-cell level.

Key Points Question Can circulating microRNAs be used to derive clinically significant noninvasive diagnostic biomarkers for gastric cancer? Findings This diagnostic study used a multistep and comprehensive biomarker discovery approach to establish a novel, noninvasive, microRNA-based signature for the early detection of gastric cancer, which was retrospectively and prospectively validated in multicenter patient cohorts. Meaning For patients with gastric cancer and individuals with a high risk for gastric cancer, a microRNA-based signature may improve the early detection of gastric cancer., This diagnostic study describes the development and validation of a microRNA-based liquid biopsy assay for early detection of gastric cancer., Importance Noninvasive detection of early-stage disease is a key strategy for reducing gastric cancer (GC)-associated patient mortality. Objective To establish a novel, noninvasive, microRNA (miRNA)-based signature for the early detection of GC using a comprehensive biomarker discovery approach with retrospective and prospective validation. Design, Setting, and Participants This diagnostic study was conducted in 4 phases using publicly available genome sequences and tissue samples from patients at an academic medical center in Japan, and validated with retrospective multicenter cohorts of patients with GC. Three tissue miRNA data sets were used to identify a miRNA signature that discriminated GC vs normal tissues. The robustness of this signature was assessed in serum from 2 retrospective cohorts of patients with GC. A risk-scoring model was derived, then the performance of the miRNA signature was evaluated in a prospective cohort of patients with GC. The robustness of the miRNA signature was compared with current blood-based markers, and a cost-effectiveness analysis of the miRNA signature against the current practice of endoscopy was performed. All clinical samples used for this study were collected and data analyzed between April 1997 and March 2018. Main Outcomes and Measures Assessment of diagnostic efficiency on the basis of area under the curve (AUC), specificity, and sensitivity. Results The data sets for the genome-wide expression profiling analysis stage included 598 total patient samples (284 [55.4%] from men; mean [SE] patient age, 65.7 [0.5] years). The resulting 10-miRNA signature was validated in 2 retrospective GC serum cohorts (586 patients; 348 [59.4%] men, mean [SE] age, 66.0 [0.7] years), which led to the establishment of a 5-miRNA signature (AUC, 0.90; 95% CI, 0.85-0.94) that also exhibited high levels of diagnostic performance in patients with stage I disease (AUC, 0.89; 95% CI, 0.83-0.94). A risk-scoring model was derived and the assay was optimized to a minimal number of miRNAs. The performance of the resulting 3-miRNA signature was then validated in a prospective cohort of patients with GC (349 patients; 124 [70.5%] men, median [range] age, 66.0 [0.66] years). The final 3-miRNA signature (miR-18a, miR-181b, and miR-335) exhibited high diagnostic accuracy in all stages of patients (AUC, 0.86; 95% CI 0.83-0.90), including in patients with stage I disease (AUC, 0.85; 95% CI, 0.79-0.91). Furthermore, this miRNA signature was superior to currently used blood markers and outperformed the endoscopic screening in a cost-effectiveness analysis (incremental cost-effectiveness ratio, CNY ¥16162.5 per quality-adjusted life-year [USD $2304.80 per quality-adjusted life-year]). Conclusions and Relevance These results suggest the potential clinical significance of the 3-miRNA signature as a noninvasive, cost-effective, and facile assay for the early detection of GC.

Southern China was a region with mixed rice-millet farming during the Middle Neolithic period and also suggested to be the homeland of Tai-Kadai-speaking (TK) people. The archaeological evidence of animal and plant domestication has demonstrated that southern Chinese rice agriculturalists dispersed from the Yangtze River basin with the dissemination of TK, Austroasiatic (AA), Austronesian (AN) and Hmong-Mien (HM) languages. However, the formations of the inland TK-speaking people, central/southern Han Chinese and their relationships with Neolithic farmers from the Yangtze and Yellow Rivers (YR) basins are far from clear due to the limited sampling of South China. Here, we revealed the spatiotemporal demographic history of southern China by analyzing newly generated genome-wide data of 70 southeastern mainland TK speakers including Dong, Gelao and Bouyei and 45 southwestern Han Chinese together with comprehensive modern/ancient reference datasets. Southwest Han Chinese and Gelao demonstrated a closer genomic affinity to Neolithic YR farmers, while inland TKs (Dong and Bouyei) demonstrated a closer genomic affinity to coastal TK/AN-speaking islanders and Neolithic Yangtze farmers and their descendants. The shared genetic drift between inland TK/AN speaker highlighted a common origin of AN/TK groups, which may be descended from Tanshishan people or their predecessors (Xitoucun). Additionally, we found that inland TK/Sinitic could be modelled as an admixture of ancestral northern East Asian (ANEA) and ancestral southern East Asian (ASEA) sources with different proportions, in which the ANEA was phylogenetically closer to Neolithic millet farmers deriving from the YR Basin and the ASEA was phylogenetically closer to Coastal Neolithic-to-modern southern East Asians. Finally, we discovered genetic differentiation among TK people from southern China and Southeast Asia and obvious substructures between northern and southern inland Chinese TK people. The observed patterns of the spatiotemporal distribution of the northern and southern East Asian lineages in Central/southern China were also compatible with the scenario of bi-directional gene flow events from ANEA and ASEA. Conclusively, multiple lines of genomic evidence indicated millet farmers deriving from the YR basin and rice farmers deriving from the Yangtze River basin substantially contributed to the present-day mainland TK speakers and Central/southern Han Chinese, and formed the modern dual genetic admixture profile.

Backgrounds Genome-wide association studies (GWAS) have identified multiple common CRC-related (colorectal cancer) SNPs (single nucleotide polymorphisms) including the Cadherin 1(CDH1) rs9929218 may act by increasing the risk of colorectal cancer, colorectal adenoma, or both. These studies, however, reported inconsistent associations. Methods To derive a more accurate approximation of the connection, we carried out a meta-analysis of 12 published pieces of research including 11,590 controls and 8192 cases. We used odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the associations’ strength. Results Meta-analysis implied considerable association between CRC and rs9929218 (OR = 1.21, 95%CI 1.04–1.42 for GG versus AA; OR = 1.22, 95%CI 1.05–1.42 for GG/AG versus AA). In the subgroup analyses, significantly increased risks were found among Europeans. Conclusions In summary, our meta-analysis studies in different populations confirmed that SNP rs9929218 is significantly associated with CRC risk and that this variant may have a greater impact on Europeans.

Objective: To investigate the role and functions of FAM225A in gastric cancer. Methods: The expressions of FAM225A, miR-206, ADAM12 and epithelial-mesenchymal transition (EMT)-related genes were detected by quantitative real-time PCR and Western blot. Functional experiments including cell counting kit-8, colony formation, wound-healing, and Transwell assays were conducted to analyze the biological characteristics of gastric cancer cells in different groups. Bioinformatics, dual-luciferase reporter assay and Pearson correlation coefficients were performed for determining the regulatory relationship of lncRNA-miRNA-mRNA. In vivo nude mouse xenografts and immunohistochemistry were used to verify the results in vitro. Results: In gastric cancer, FAM225A and ADAM12 expressions were up-regulated, while miR-206 expression was down-regulated. Opposite to the regulatory effects of overexpressed FAM225A, blocking FAM225A expression reduced cell viability, migration, invasion and number of cell clones, increased E-Cadherin expression, inhibited N-Cadherin and Vimentin expressions, and ultimately promoted tumor growth. MiR-206 inhibitor partially offset the effects of siFAM225A. Moreover, FAM225A competitively bound to miR-206 to up-regulate ADAM12 expression. Overexpressed ADAM12 partially reversed the effect of miR-206 mimic on the biological characteristics of gastric cancer cells and EMT-related proteins. Conclusion: Our research revealed that FAM225A-miR-206-ADAM12 axis may be a potential pathway for regulating gastric cancer.

Purpose Gastric hepatoid adenocarcinoma is a rare subtype of primary gastric cancer and is a high-grade form of malignancy. However, the pathogenesis and molecular biology of gastric hepatoid adenocarcinoma remain poorly understood. The aim of this study was to establish and characterize a new human gastric hepatoid adenocarcinoma cell line, GC-030-35. Materials and methods The GC-030-35 cell line was established from tumor cells from a 58-year-old Chinese man with gastric hepatoid adenocarcinoma. The cultured cells underwent immunocytochemistry and flow cytometry to confirm the tumor cell phenotype. RNA sequencing was performed to analyze the differences in gene expression between GC-030-35 cells compared with normal gastric epithelial cells. A zebrafish assay was performed. Gene enrichment analysis and interrogation of the bioinformatics databases, the Gene Ontology (GO) database and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, were used for pathway analysis. Results Flow cytometry analysis of the GC-030-35 cells showed a positive expression rate for CD44+ of 10.7%, high cell clonality, an average plating efficiency of 32%, cell-doubling time of 29.2 hours, and cell proliferation for >15 generations in serial culture. The zebrafish assay showed the ability of the GC-030-35 cells to proliferate, promote angiogenesis, and metastasize. RNA sequencing identified the functional clustering of 6,601 differentially expressed genes of GC-030-35, which were significantly different when compared with nonneoplastic gastric epithelial cells. Pathway enrichment analysis and interrogation of the GO and KEGG bioinformatics databases identified genes for microbial metabolism in diverse environments (63 genes), metabolism of xenobiotics by cytochrome P450 (CYP450; 25 genes), and the drug metabolism cytochrome P450 (28 genes). Conclusion A human gastric hepatoid adenocarcinoma cell line, GC-030-35, was developed and characterized by comparison with normal gastric epithelial cells. Bioinformatics and gene analysis data showed that the CYP450 gene was significantly differentially expressed by GC-030-35 cells.

Long non-coding RNAs (lncRNAs) have appeared as vital regulatory factors in different pathological processes, particularly in tumorigenesis. Increasing number of evidence has demonstrated that long intergenic non-coding RNA 00662 (LINC00662) is overexpressed in several types of cancers and promotes cancer initiation and development. However, whether LINC00662 participates in colorectal cancer (CRC) remains unclear. This study was aimed to explore the expression, biological function and regulatory mechanism of LINC00662 in CRC. Here, we found that LINC00662 expression was obviously upregulated in CRC tissues and cell lines. Down-regulation of LINC00662 dramatically inhibited the growth of CRC cells and increased CRC cell apoptosis.MicroRNA-145 (miR-145) was speculated as a target miRNA of LINC00662 by bioinformatics analysis. Luciferase reporter assays and RNA pull-down assays verified that LINC00662 directly interacted with miR-145. Expression of miR-145 was downregulated in CRC tissues and cell lines. Up-regulation of miR-145suppressed cell growth and promoted apoptosis in CRC cells. Suppression of miR-145markedly reversed the suppressive function of LINC00662 knockdown on CRC cell growth. In addition, c-myc was confirmed as a target gene of miR-145 in CRC cells. Recover of c-myc expression partially reversed suppression effect mediated by LINC00662 downexpression or miR-145overexpressionon CRC cell growth. Taken together, our results indicate that LINC00662lead to the malignant behavior of CRC cells by upregulating c-myc via sponging miR-145, underlining the essential role of the LINC00662/miR-145/c-myc axis in regulating the growth of CRC cells.

Long noncoding RNAs (LncRNAs) have been reported to play critical roles in gastric cancer, but true biomarkers remain unknown. In this study, we found a new lncRNA LINC00355 that was involved in malignant progression of gastric cancer (GC) and further revealed its role and mechanism. Differentially expressed lncRNAs were identified through bioinformatics, and qRT-PCR was used to validate the expression of LINC00355 in gastric cancer tissues and cells. The biological role of LINC00355 in GC was detected by gene overexpression and knockdown experiments. Subcellular fractionation, qRT-PCR, and FISH were performed to detect the subcellular localization. Co-IP and western blotting were used to study the ubiquitination-mediated regulation of P53 and the expression of the E3 ligases RAD18 and UBE3C. The results showed that LINC00355 was significantly increased in gastric cancer cell lines and patient tissues and closely correlated with late stages, distant metastasis, and poor prognosis of patients. High expression of LINC00355 promoted the proliferation and invasion of gastric cancer cells in vivo and in vitro. Mechanistic studies found that LINC00355 that mainly located in the nucleus, acting as a transcriptional activator, promoted transcription of RAD18 and UBE3C, which both bind to P53 and mediate the ubiquitination and degradation of P53. Furthermore, LINC00355 overexpression enhanced the ubiquitination process, and LINC00355 knockdown alleviated it. These results indicated that LINC00355 induces gastric cancer cell proliferation and invasion by promoting transcription of RAD18 and UBE3C, which mediates ubiquitination of P53 and thereby plays a critical role in survival and tumorigenicity of gastric cancer cells. LINC00355 may represent a new mechanism for GC progression and provide a potential marker for GC diagnosis and treatment.

The integrated analytical strategy identified both genetic and epigenetic biomarkers for gastric cancer etiology., The biological effects of susceptibility loci are rarely reported in gastric tumorigenesis. We conducted a large-scale cross-ancestry genetic study in 18,852 individuals and identified the potential causal variant rs3850997 T>G at 16p13 significantly associated with a decreased risk of gastric cancer [odds ratio (OR) = 0.87, 95% confidence interval (CI) = 0.83 to 0.91, P = 2.13 × 10−9]. This risk effect was mediated through the mapped long noncoding RNA GCLET (Gastric Cancer Low-Expressed Transcript; ORindirect = 0.987, 95% CI = 0.975 to 0.999, P = 0.018). Mechanistically, rs3850997 exerted an allele-specific long-range regulatory effect on GCLET by affecting the binding affinity of CTCF. Furthermore, GCLET increased FOXP2 expression by competing with miR-27a-3p, and this regulation remarkably affected in vitro, in vivo, and clinical gastric cancer phenotypes. The findings highlight the genetic functions and implications for the etiology and pathology of cancers.

Objective: This study was undertaken to investigate the effect of C225 on the radio-sensitivity of MDA-MB-231 cells line and to disclosure underlying mechanism. Methods: CCK8 assay was used to measure the proliferation inhibition of C225 on MDA-MB-231 cells. The combined effects of C225 plus radiation on the proliferation of MDA-MB-231 cells were also evaluated by CCK-8 assay. The clonogenic assay was performed to evaluate the cell surviving fractions and to determine the radio-sensitizing effect of C225 on MDA-MB-231 cells. The apoptosis and cell cycle distribution were analyzed by flow cytometry. Western blot analysis was used to detect the expression of p-EGFR, p-Akt, p-P38, and caspase-3. Results: C225 had an inhibiting effect on the proliferation of cells in a concentration-dependent manner. The cloning formation capacity was decreased in C225 plus radiation group. C225 increased radio-sensitivity of cells and led to cell cycle arrest in G0/G1 phase markedly. Cells treated with C225 and radiation predominantly exhibited G0/G1 phase arrest and significant decreased in the fraction of cells in the S phase. Moreover, C225 and radiation significantly increased the apoptosis rate of cells. Decreased cell proliferation was further supported by the down-regulation of p-EGFR and its downstream singling pathway proteins such as p-Akt and p-P38. The up-regulation of the Caspase-3 expression in C225 plus radiation group revealed that C225 could increase radiation-inducing cell apoptosis. Conclusion: C225 could increase the radio-sensitivity of cells, which may be due to the anti-proliferative synergistic effect between C225 and radiation as well as the down-regulation of the PI3K/Akt signaling pathway.