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1.
Proc Natl Acad Sci U S A ; 119(5)2022 02 01.
Article in English | MEDLINE | ID: mdl-35091468

ABSTRACT

Lysosome plays important roles in cellular homeostasis, and its dysregulation contributes to tumor growth and survival. However, the understanding of regulation and the underlying mechanism of lysosome in cancer survival is incomplete. Here, we reveal a role for a histone acetylation-regulated long noncoding RNA termed lysosome cell death regulator (LCDR) in lung cancer cell survival, in which its knockdown promotes apoptosis. Mechanistically, LCDR binds to heterogenous nuclear ribonucleoprotein K (hnRNP K) to regulate the stability of the lysosomal-associated protein transmembrane 5 (LAPTM5) transcript that maintains the integrity of the lysosomal membrane. Knockdown of LCDR, hnRNP K, or LAPTM5 promotes lysosomal membrane permeabilization and lysosomal cell death, thus consequently resulting in apoptosis. LAPTM5 overexpression or cathepsin B inhibitor partially restores the effects of this axis on lysosomal cell death in vitro and in vivo. Similarly, targeting LCDR significantly decreased tumor growth of patient-derived xenografts of lung adenocarcinoma (LUAD) and had significant cell death using nanoparticles (NPs)-mediated systematic short interfering RNA delivery. Moreover, LCDR/hnRNP K/LAPTM5 are up-regulated in LUAD tissues, and coexpression of this axis shows the increased diagnostic value for LUAD. Collectively, we identified a long noncoding RNA that regulates lysosome function at the posttranscriptional level. These findings shed light on LCDR/hnRNP K/LAPTM5 as potential therapeutic targets, and targeting lysosome is a promising strategy in cancer treatment.


Subject(s)
Heterogeneous-Nuclear Ribonucleoprotein K/metabolism , Membrane Proteins/metabolism , RNA, Long Noncoding/genetics , Apoptosis/genetics , Cell Death , Cell Line, Tumor , Cell Survival , China , Gene Expression/genetics , Gene Expression Regulation, Neoplastic/genetics , Heterogeneous-Nuclear Ribonucleoprotein K/genetics , Humans , Intracellular Membranes/metabolism , Lysosomes/metabolism , Neoplasms/genetics
2.
BMC Cancer ; 23(1): 642, 2023 Jul 10.
Article in English | MEDLINE | ID: mdl-37430229

ABSTRACT

Assessing long-term tumor survival rates is crucial for evaluating the effectiveness of tumor treatment and burden. However, timely assessment of long-term survival in patients with pancreatic cancer is lagging in China. In this study, we applied period analysis to estimate the long-term survival of pancreatic cancer patients using data from four population-based cancer registries in Taizhou city, eastern China. A total of 1121 patients diagnosed with pancreatic cancer between 2004 and 2018 were included. We assessed the 5-year relative survival (RS) using period analysis and further stratified by sex, age at diagnosis, and region. The 5-year RS during 2014-2018 overall reached 18.9% (14.7% for men and 23.3% for women, respectively). A decrease of the 5-year RS from 30.3% to 11.2% was observed in four diagnostic age gradients (< 55, 55-64, 65-74, and > 74 years age groups). The 5-year RS was higher in urban (24.2%) than in rural (17.4%) areas. Moreover, the 5-year RS of pancreatic cancer patients showed an overall increasing trend for the three periods (2004-2008, 2009-2013, and 2014-2018). Our study, using period analysis for the first time in China, provides the latest estimates of the survival of patients with pancreatic cancer, which provides essential evidence for the prevention and intervention of pancreatic cancer. The results also indicate the importance of further applications of the period analysis for more up-to-date and accurate survival estimates.


Subject(s)
Pancreatic Neoplasms , Male , Humans , Female , Aged , Pancreatic Neoplasms/epidemiology , Pancreatic Neoplasms/therapy , China/epidemiology , Patients , Demography , Pancreatic Neoplasms
3.
BMC Cancer ; 21(1): 190, 2021 Feb 24.
Article in English | MEDLINE | ID: mdl-33627078

ABSTRACT

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.


Subject(s)
Adenoma/genetics , Cadherins/genetics , Colorectal Neoplasms/genetics , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Adenoma/etiology , Colorectal Neoplasms/etiology , Genome-Wide Association Study , Humans , Publication Bias , Risk
4.
J Cell Mol Med ; 24(21): 12525-12536, 2020 11.
Article in English | MEDLINE | ID: mdl-33047871

ABSTRACT

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.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/therapeutic use , Sorafenib/therapeutic use , Stilbenes/therapeutic use , Stomach Neoplasms/drug therapy , Adenocarcinoma/pathology , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Autophagy/drug effects , Cell Death/drug effects , Cell Line, Tumor , Cell Shape/drug effects , Cell Survival/drug effects , Drug Synergism , G1 Phase Cell Cycle Checkpoints/drug effects , Male , Mice, Inbred BALB C , Mice, Nude , Sorafenib/pharmacology , Stilbenes/chemistry , Stilbenes/pharmacology , Stomach Neoplasms/pathology , Xenograft Model Antitumor Assays
5.
Zhonghua Nan Ke Xue ; 26(7): 588-594, 2020 Jul.
Article in Zh | MEDLINE | ID: mdl-33377712

ABSTRACT

OBJECTIVE: To investigate the expression of Linc00662 in PCa and its influence on the biological function of PCa cells. METHODS: Using qRT-PCR, we detected the expression of Linc00662 in the PCa tissue and cell lines and that in the adjacent normal prostatic tissue and epithelial WPMY-1 cells and analyzed the correlation between the expression of Linc00662 and the clinicopathological features of the PCa tissue. We transfected PC-3 and DU145 cells with siRNA, and verified the interference efficiency by qRT-PCR. We examined the effects of interfering with the Linc00662 expression on the proliferation, apoptosis, migration and invasiveness of PC-3 and DU145 cells by CCK-8 assay, Caspase 3/9 activity assay, wound-healing assay and Transwell invasion assay. RESULTS: The expression of Linc00662 in the PCa tissue and cell lines was significantly up-regulated compared with that in the adjacent normal prostatic tissue and epithelial cells (P < 0.01), and the high expression of Linc00662 was positively correlated with the tumor stage (P = 0.002), primary tumor size (P = 0.006), lymph node metastasis (P = 0.001) and distant metastasis (P = 0.001). Transfection of si-Linc00662 into the PC-3 and DU145 cells significantly reduced the expression of Linc00662 (P < 0.01). Compared with the normal control, the PC-3 and DU145 cells in the Linc00662 interference group showed remarkably decreased proliferation, invasion and migration abilities (P < 0.01), but an increased rate of apoptosis (P < 0.01). CONCLUSIONS: Linc00662 is highly expressed in PCa tissues and cells relatively. Knockdown of the Linc00662 expression may inhibit the proliferation, migration and invasiveness and promote the apoptosis of PCa cells. Therefore, Linc00662 could be considered as a new marker of PCa.


Subject(s)
Carcinogenesis , Prostatic Neoplasms , RNA, Long Noncoding , Apoptosis , Cell Line, Tumor , Cell Movement , Cell Proliferation , Gene Expression Regulation, Neoplastic , Humans , Male , Prostatic Neoplasms/genetics , RNA, Long Noncoding/genetics , RNA, Small Interfering
6.
Hum Genomics ; 12(1): 40, 2018 08 22.
Article in English | MEDLINE | ID: mdl-30134973

ABSTRACT

BACKGROUND: Massive occurrences of interstitial loss of heterozygosity (LOH) likely resulting from gene conversions were found by us in different cancers as a type of single-nucleotide variations (SNVs), comparable in abundance to the commonly investigated gain of heterozygosity (GOH) type of SNVs, raising the question of the relationships between these two opposing types of cancer mutations. METHODS: In the present study, SNVs in 12 tetra sample and 17 trio sample sets from four cancer types along with copy number variations (CNVs) were analyzed by AluScan sequencing, comparing tumor with white blood cells as well as tissues vicinal to the tumor. Four published "nontumor"-tumor metastasis trios and 246 pan-cancer pairs analyzed by whole-genome sequencing (WGS) and 67 trios by whole-exome sequencing (WES) were also examined. RESULTS: Widespread GOHs enriched with CG-to-TG changes and associated with nearby CNVs and LOHs enriched with TG-to-CG changes were observed. Occurrences of GOH were 1.9-fold higher than LOH in "nontumor" tissues more than 2 cm away from the tumors, and a majority of these GOHs and LOHs were reversed in "paratumor" tissues within 2 cm of the tumors, forming forward-reverse mutation cycles where the revertant LOHs displayed strong lineage effects that pointed to a sequential instead of parallel development from "nontumor" to "paratumor" and onto tumor cells, which was also supported by the relative frequencies of 26 distinct classes of CNVs between these three types of cell populations. CONCLUSIONS: These findings suggest that developing cancer cells undergo sequential changes that enable the "nontumor" cells to acquire a wide range of forward mutations including ones that are essential for oncogenicity, followed by revertant mutations in the "paratumor" cells to avoid growth retardation by excessive mutation load. Such utilization of forward-reverse mutation cycles as an adaptive mechanism was also observed in cultured HeLa cells upon successive replatings. An understanding of forward-reverse mutation cycles in cancer development could provide a genomic basis for improved early diagnosis, staging, and treatment of cancers.


Subject(s)
DNA Copy Number Variations/genetics , Genome, Human/genetics , Loss of Heterozygosity/genetics , Neoplasms/genetics , Genomics , HeLa Cells , High-Throughput Nucleotide Sequencing , Humans , Mutation , Neoplasms/pathology , Polymorphism, Single Nucleotide , Exome Sequencing
7.
Nucleic Acids Res ; 45(6): 3086-3101, 2017 04 07.
Article in English | MEDLINE | ID: mdl-27956498

ABSTRACT

Recently, long non-coding RNAs (lncRNAs) have been shown to have important regulatory roles in human cancer biology. In our study, we found that lncRNA CCAT1, whose expression is significantly increased and is correlated with outcomes in Esophageal Squamous Cell Carcinoma (ESCC). Consecutive experiments confirmed that H3K27-acetylation could activate expression of colon cancer associated transcript-1 (CCAT1). Further experiments revealed that CCAT1 knockdown significantly repressed the proliferation and migration both in vitro and in vivo. RNA-seq analysis revealed that CCAT1 knockdown preferentially affected genes that are linked to cell proliferation, cell migration and cell adhesion. Mechanistic investigations found that CCAT1 could serve as a scaffold for two distinct epigenetic modification complexes (5΄ domain of CCAT1 binding Polycomb Repressive Complex 2 (PRC2) while 3΄ domain of CCAT1 binding SUV39H1) and modulate the histone methylation of promoter of SPRY4 (sprouty RTK signaling antagonist 4) in nucleus. In cytoplasm, CCAT1 regulates HOXB13 as a molecular decoy for miR-7, a microRNA that targets both CCAT1 and HOXB13, thus facilitating cell growth and migration. Together, our data demonstrated the important roles of CCAT1 in ESCC oncogenesis and might serve as targets for ESCC diagnosis and therapy.


Subject(s)
Carcinoma, Squamous Cell/genetics , Esophageal Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Histones/metabolism , Homeodomain Proteins/genetics , Intracellular Signaling Peptides and Proteins/genetics , Nerve Tissue Proteins/genetics , RNA, Long Noncoding/metabolism , Acetylation , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Cell Line, Tumor , Cell Movement , Cell Proliferation , Enhancer of Zeste Homolog 2 Protein/metabolism , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/pathology , Esophageal Squamous Cell Carcinoma , Female , Gene Silencing , Homeodomain Proteins/metabolism , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Male , Methyltransferases/metabolism , MicroRNAs/metabolism , Middle Aged , Nerve Tissue Proteins/metabolism , Prognosis , RNA, Long Noncoding/physiology , Repressor Proteins/metabolism
8.
J Cell Mol Med ; 22(11): 5220-5230, 2018 11.
Article in English | MEDLINE | ID: mdl-30179299

ABSTRACT

Oestrogen receptor (ER) is expressed in approximately 60%-70% of human breast cancer. Clinical trials and retrospective analyses have shown that ER-positive (ER+) tumours are more tolerant to chemotherapeutic drug resistance than ER-negative (ER-) tumours. In addition, isobavachalcone (IBC) is known as a kind of phytoestrogen with antitumour effect. However, the underlying mechanism of IBC in ER+ breast cancer needs to be elucidated further. Our in vitro experiments showed that IBC could attenuate 17ß-estradiol (E2 )-induced paclitaxel resistance and that E2 could stimulate CD44 expression in ER+ breast cancer cells but not in ER- cells. Meanwhile, E2 could promote ERα expression to render ER+ breast cancer cells resistant to paclitaxel. Furthermore, we established paclitaxel-resistant breast cancer cell lines and determined the function of ERα in the enhancement of paclitaxel resistance via the regulation of CD44 transcription. IBC down-regulated ERα and CD44 expression and thus inhibited tumour growth in paclitaxel-resistant xenograft models. Overall, our data demonstrated for the first time that IBC could decrease CD44 expression level via the ERα pathway and make ER+ breast cancer cells sensitive to paclitaxel treatment.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Breast Neoplasms/drug therapy , Chalcones/pharmacology , Estrogen Receptor alpha/genetics , Apoptosis/drug effects , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Proliferation/drug effects , Drug Resistance, Neoplasm/genetics , Estradiol/metabolism , Estradiol/pharmacology , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Hyaluronan Receptors/genetics , MCF-7 Cells , Paclitaxel/adverse effects , Paclitaxel/pharmacology
9.
Mol Cancer ; 17(1): 6, 2018 01 12.
Article in English | MEDLINE | ID: mdl-29329543

ABSTRACT

BACKGROUND: Long noncoding RNAs (lncRNAs) are an important class of functional regulators involved in human cancers development, including gastric cancer (GC). Studying aberrantly expressed lncRNAs may provide us with new insights into the occurrence and development of gastric cancer by acting as oncogenes or tumor suppressors. In this study, we aim to examine the expression pattern of lncRNA HAGLROS in GC and its clinical significance as well as its biological role in tumor progression. METHODS: Bioinformatics analysis and qRT-PCR were performed to detect the relative expression of HAGLROS in GC tissues and cell lines. Gain or loss of function approaches were used to investigate the biological functions of HAGLROS. The effect of HAGLROS on proliferation was evaluated by MTT, colony formation assay and nude mouse xenograft model. Wound healing and Transwell assays were used to study the invasion and migration of GC cells. FISH, RIP, RNA-seq, Luciferase report assays, RNA pulldown and Western blot were fulfilled to measure molecular mechanisms. Results are shown as means ± S.D. and differences were tested for significance using Student's t-test (two-tailed). RESULTS: We screened out HAGLROS, whose expression was significantly increased and correlated with outcomes of GC patients by publicly available lncRNAs expression profiling and integrating analyses. Exogenous down-regulation of HAGLROS expression significantly suppressed the cell proliferation, invasion and migration. Mechanistic investigations showed that HAGLROS was a direct target of transcriptional factor STAT3. Moreover, HAGLROS knockdown decreased mTOR expression and increased autophagy-related genes ATG9A and ATG9B expression. Further investigation showed that HAGLROS regulated mTOR signals in two manners. In the one hand, HAGLROS competitively sponged miR-100-5p to increase mTOR expression by antagonizing miR-100-5p-mediated mTOR mRNA inhibition. On the other hand, HAGLROS interacted with mTORC1 components to activate mTORC1 signaling pathway which was known to be an important negative signal of autophagy. Here activation of mTORC1 signaling pathway by HAGLROS inhibited autophagy, thereby promoted excessive proliferation and maintained the malignant phenotype of GC cells. CONCLUSION: The present study demonstrates that HAGLROS overexpression contributes to GC development and poor prognosis and will be a target for GC therapy and further develop as a potential prognostic biomarker.


Subject(s)
Autophagy , Gene Expression Regulation, Neoplastic , RNA, Long Noncoding/genetics , STAT3 Transcription Factor/metabolism , Signal Transduction , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , TOR Serine-Threonine Kinases/metabolism , Animals , Binding Sites , Cell Line, Tumor , Cell Movement , Cell Proliferation , Cell Transformation, Neoplastic , Databases, Genetic , Disease Models, Animal , Disease Progression , Gene Expression Profiling , Heterografts , Humans , Mechanistic Target of Rapamycin Complex 1/metabolism , Mice , Nucleotide Motifs , Prognosis , Protein Binding
10.
Gastroenterology ; 152(8): 2011-2021, 2017 06.
Article in English | MEDLINE | ID: mdl-28246015

ABSTRACT

BACKGROUND & AIMS: Several genetic variants have been associated with gastric cancer risk, although these account for only a fraction of cases of gastric cancer. We aimed to identify low-frequency and other genetic variants that determine gastric cancer susceptibility. METHODS: We performed exome array analysis of DNA in blood samples from 1113 patients with gastric cancer, collected at hospitals from 2006 to 2010 in China, and 1848 individuals without cancer (controls) undergoing physical examinations. Among 71,290 variants analyzed (including 25,784 common variants), 24 variants were selected and replicated in an analysis of DNA in blood samples from 4687 additional cases of gastric cancer and 5780 controls. We compared expression of candidate genes in tumor vs normal gastric tissues using data from TCGA and performed functional annotation analyses. An immortalized human gastric epithelial cell line (GES1) and 7 human gastric cancer lines were used to express transgenes, knock down gene expression (with small interfering RNAs), disrupt genes (using the CRISPR/Cas9 system), or assess expression of reporter constructs. We measured cell proliferation, colony formation, invasion, and migration, and assessed growth of xenograft tumors in nude mice. RESULTS: A low-frequency missense variant rs112754928 in the SPOC domain containing 1 gene (SPOCD1; encoding p.Arg71Trp), at 1p35.2, was reproducibly associated with reduced risk of gastric cancer (odds ratio, 0.56; P = 3.48 × 10-8). SPOCD1 was overexpressed in gastric tumors, and knockout of SPOCD1 reduced gastric cancer cell proliferation, invasive activity, and migration, as well as growth of xenograft tumors in nude mice. We also associated the variant rs1679709 at 6p22.1 with reduced risk for gastric cancer (odds ratio, 0.80; P = 1.17 × 10-13). The protective allele rs1679709-A correlated with the surrounding haplotype rs2799077-T-rs2799079-C, which reduced the enhancer activity of this site to decrease expression of the butyrophilin subfamily 3 member A2 gene (BTN3A2). BTN3A2 is overexpressed in gastric tumors, and deletion of BTN3A2 inhibited proliferation, migration, and invasion of gastric cancer cells. CONCLUSIONS: We have associated variants at 1p35.2 and 6p22.1 with gastric cancer risk, indicating a role for SPOCD1 and BTN3A2 in gastric carcinogenesis.


Subject(s)
Biomarkers, Tumor/genetics , Butyrophilins/genetics , Exosomes/genetics , Genetic Variation , Stomach Neoplasms/genetics , Aged , Animals , Biomarkers, Tumor/metabolism , Butyrophilins/metabolism , CRISPR-Cas Systems , Case-Control Studies , Cell Line, Tumor , Cell Movement , Cell Proliferation , China , Female , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Logistic Models , Male , Mice, Inbred BALB C , Mice, Nude , Middle Aged , Multivariate Analysis , Neoplasm Invasiveness , Odds Ratio , Phenotype , RNA Interference , Risk Factors , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Time Factors , Transfection , Tumor Burden
11.
Biochem Biophys Res Commun ; 507(1-4): 223-230, 2018 12 09.
Article in English | MEDLINE | ID: mdl-30448060

ABSTRACT

Long non-coding RNAs (lncRNAs) are a crucial member of the non-coding RNA family, and increasing evidence demonstrates that lncRNAs participate in the initiation and progression of cancers. Our study aimed to explore the role of the lncRNA LINC00165 in gastric cancer (GC) development. In the present study, our results showed that LINC00165 was upregulated in GC tissues and cell lines and high expression of LINC00165 was correlated with tumor-node-metastasis stage, invasion depth, and overall survival of GC patients. Functional assays showed that LINC00165 knockdown inhibited the proliferation, migration and invasion of GC cells and LINC00165 overexpression stimulated their proliferation, migration and invasion. Online transcription factor binding site prediction analysis showed that there were STAT3 binding sites in the LINC00165 promoter region. Furthermore, luciferase reporter and chromatin immunoprecipitation assays provided evidence that STAT3 could bind directly to the region between -547 bp to -537 bp (ATGTTGGGAAA) of LINC00165 promoter and activate its transcription. Then GC cells were partitioned into nuclear and cytoplasmic fractions and we found that LINC00165 was localized preferentially to the nucleus. Mechanistically, we revealed that LINC00165 functioned as a scaffold for interaction with Polycomb Repressive Complex 2 to promote the epithelial-mesenchymal transition in GC cells. Taken together, our study revealed that LINC00165 was involved in the progression and poor prognosis of GC as an oncogenic role. Therefore, LINC00165 might become a new potential target for GC chemotherapy and further predict prognosis of patients.


Subject(s)
Epithelial-Mesenchymal Transition/genetics , Oncogenes , Polycomb Repressive Complex 2/metabolism , RNA, Long Noncoding/metabolism , STAT3 Transcription Factor/metabolism , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Aged , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Cell Survival/genetics , Disease-Free Survival , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Middle Aged , Multivariate Analysis , Neoplasm Invasiveness , Neoplasm Staging , Prognosis , Promoter Regions, Genetic/genetics , RNA, Long Noncoding/genetics , Tumor Stem Cell Assay , Up-Regulation/genetics
12.
Invest New Drugs ; 36(2): 315-322, 2018 04.
Article in English | MEDLINE | ID: mdl-29134432

ABSTRACT

Background Dulanermin is a recombinant soluble human Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that activates apoptotic pathways by binding to proapoptotic death receptor (DR) 4 and DR5. The purpose of this study was to evaluate the efficacy and safety of dulanermin combined with vinorelbine and cisplatin (NP) as the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). Experimental design Patients were randomly assigned to receive NP chemotherapy (vinorelbine 25 mg/m2 on days 1 and 8 and cisplatin 30 mg/m2 on days 2 to 4) for up to six cycles plus dulanermin (75 µg/kg on days 1 to 14) or placebo every three weeks until disease progression, intolerable toxicity, or withdrawal of consent. The primary end point was progression-free survival (PFS), and the secondary end points included objective response rate (ORR), overall survival (OS), and safety evaluation. Results Between October 2009 and June 2012, 452 untreated patients with stage IIIB to IV NSCLC were randomly assigned to receive dulanermin plus NP (n = 342) and placebo plus NP (n = 110). Median PFS was 6.4 months in the dulanermin arm versus 3.5 months in the placebo arm (hazard ratio (HR), 0.4034; 95% CI, 0.3181 to 0.5117, p < 0.0001). ORR was 46.78% in the dulanermin arm versus 30.00% in the placebo arm (p = 0.0019). Median OS was 14.6 months in the dulanermin arm versus 13.9 months in the placebo arm (HR, 0.94; 95% CI, 0.74 to 1.21, p = 0.64). The most common grade ≥ 3 adverse events (AEs) were oligochromemia, leukopenia, neutropenia, and oligocythemia. Overall incidence of AEs, grade ≥ 3 AEs, and serious AEs were similar across the two arms. Conclusion Addition of dulanermin to the NP regimen significantly improved PFS and ORR. However, our results showed that the combination of dulanermin with chemotherapy had a synergic activity and favorable toxic profile in the treatment of patients with advanced NSCLC.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Cisplatin/therapeutic use , Lung Neoplasms/drug therapy , TNF-Related Apoptosis-Inducing Ligand/therapeutic use , Vinorelbine/therapeutic use , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/pathology , Cisplatin/adverse effects , Female , Humans , Kaplan-Meier Estimate , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , TNF-Related Apoptosis-Inducing Ligand/adverse effects , Treatment Outcome , Vinorelbine/adverse effects , Young Adult
13.
Arch Toxicol ; 92(6): 1991-1999, 2018 06.
Article in English | MEDLINE | ID: mdl-29766219

ABSTRACT

Although studies have investigated the association of genetic variants and the abnormal expression of estrogen-related genes with colorectal cancer risk, the evidence remains inconsistent. We clarified the relationship of genetic variants in estrogen metabolic pathway genes with colorectal cancer risk and survival. A case-control study was performed to assess the association of single-nucleotide polymorphisms (SNPs) in ten candidate genes with colorectal cancer risk in a Chinese population. A logistic regression model and Cox regression model were used to calculate SNP effects on colorectal cancer susceptibility and survival, respectively. Expression quantitative trait loci (eQTL) analysis was conducted using the Genotype-Tissue Expression (GTEx) project dataset. The sequence kernel association test (SKAT) was used to perform gene-set analysis. Colorectal cancer risk and rs3760806 in SULT2B1 were significantly associated in both genders [male: OR = 1.38 (1.15-1.66); female: OR = 1.38 (1.13-1.68)]. Two SNPs in SULT1E1 were related to progression-free survival (PFS) [rs1238574: HR = 1.24 (1.02-1.50), P = 2.79 × 10-2; rs3822172: HR = 1.30 (1.07-1.57), P = 8.44 × 10-3] and overall survival (OS) [rs1238574: HR = 1.51 (1.16-1.97), P = 2.30 × 10-3; rs3822172: HR = 1.53 (1.67-2.00), P = 2.03 × 10-3]. Moreover, rs3760806 was an eQTL for SULT2B1 in colon samples (transverse: P = 3.6 × 10-3; sigmoid: P = 1.0 × 10-3). SULT2B1 expression was significantly higher in colorectal tumor tissues than in normal tissues in the Cancer Genome Atlas (TCGA) database (P < 1.0 × 10-4). Our results indicated that SNPs in estrogen metabolic pathway genes confer colorectal cancer susceptibility and survival.


Subject(s)
Asian People/genetics , Colorectal Neoplasms/genetics , Estrogens/metabolism , Polymorphism, Single Nucleotide , Quantitative Trait Loci/genetics , Sulfotransferases/genetics , Case-Control Studies , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Female , Humans , Male , Proportional Hazards Models , Signal Transduction/genetics , Survival Analysis
14.
Arch Toxicol ; 92(8): 2681-2689, 2018 08.
Article in English | MEDLINE | ID: mdl-29968159

ABSTRACT

Circadian clock genes influence biological processes and may be involved in tumorigenesis. We systematically evaluated genetic variants in the circadian clock pathway genes associated with colorectal cancer risk and survival. We evaluated the association of 119 single nucleotide polymorphisms (SNPs) in 27 circadian clock pathway genes with the risk of colorectal cancer in a case-control study (1150 cases and 1342 controls). The false discovery rate (FDR) method was applied to correct for multiple comparisons. Gene-based analysis was performed by the sequence kernel association test (SKAT). Cox proportional hazards regression was used to calculate the effects of SNPs on the overall survival of patients. We identified that compared to those with the G allele, individuals with the rs76436997 A allele in RORA had a significant 1.33-fold increased risk of colorectal cancer (P = 3.83 × 10- 4). Specifically, the GA/AA genotypes were related to an enhanced risk of colorectal cancer compared with that associated with the GG genotype, which was more common in patients with well and moderately differentiated tumors and Dukes A/B stages. The SNP rs76436997 significantly increased the overall survival time of colorectal cancer patients (P = 0.044). Furthermore, RNA-seq data showed that the mRNA levels of RORA were significantly lower in colorectal tumors than the paired normal tissues. Gene-based analysis revealed a significant association between RORA and colorectal cancer risk. These findings highlight the important roles of genetic variations in circadian clock pathway genes play in colorectal cancer risk and suggest that RORA is potentially related to colorectal carcinogenesis.


Subject(s)
Circadian Clocks/genetics , Colorectal Neoplasms/genetics , Nuclear Receptor Subfamily 1, Group F, Member 1/genetics , Polymorphism, Single Nucleotide , Aged , Asian People , Case-Control Studies , Colorectal Neoplasms/mortality , Female , Gene Expression Regulation , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Prognosis , Survival Analysis
15.
Gut ; 66(4): 581-587, 2017 04.
Article in English | MEDLINE | ID: mdl-26701879

ABSTRACT

OBJECTIVE: Although several genome-wide association studies (GWAS) of non-cardia gastric cancer have been published, more novel association signals could be exploited by combining individual studies together, which will further elucidate the genetic susceptibility of non-cardia gastric cancer. DESIGN: We conducted a meta-analysis of two published Chinese GWAS studies (2031 non-cardia gastric cancer cases and 4970 cancer-free controls) and followed by genotyping of additional 3564 cases and 4637 controls in two stages. RESULTS: The overall meta-analysis revealed two new association signals. The first was a novel locus at 5q14.3 and marked by rs7712641 (per-allele OR=0.84, 95% CI 0.80 to 0.88; p=1.21×10-11). This single-nucleotide polymorphism (SNP) marker maps to the intron of the long non-coding RNA, lnc-POLR3G-4 (XLOC_004464), which we observed has lower expression in non-cardia gastric tumour compared with matched normal tissue (Pwilcoxon signed-rank=7.20×10-4). We also identified a new signal at the 1q22 locus, rs80142782 (per-allele OR=0.62; 95% CI 0.56 to 0.69; p=1.71×10-19), which was independent of the previously reported SNP at the same locus, rs4072037 (per-allele OR=0.74; 95% CI 0.69 to 0.79; p=6.28×10-17). Analysis of the new SNP conditioned on the known SNP showed that the new SNP remained genome-wide significant (Pconditional=3.47×10-8). Interestingly, rs80142782 has a minor allele frequency of 0.05 in East Asians but is monomorphic in both European and African populations. CONCLUSION: These findings add new evidence for inherited genetic susceptibility to non-cardia gastric cancer and provide further clues to its aetiology in the Han Chinese population.


Subject(s)
Adenocarcinoma/genetics , Asian People/genetics , Chromosomes, Human, Pair 1 , Chromosomes, Human, Pair 5 , Genetic Predisposition to Disease , Stomach Neoplasms/genetics , China , Genetic Loci , Genome-Wide Association Study , Genotype , Humans , Polymorphism, Single Nucleotide , RNA, Untranslated/genetics
16.
J BUON ; 22(4): 900-904, 2017.
Article in English | MEDLINE | ID: mdl-29155518

ABSTRACT

PURPOSE: To evaluate the efficiency and toxicity of treatment with or without cetuximab in patients with advanced gastric cancer (AGC). METHODS: Randomized phase III clinical trials (RCTs) on chemotherapy with or without cetuximab for AGC were searched in PUBMED and CNKI. A total of 874 patients were analyzed for their overall survival (OS), disease control rate (DCR), and toxicity. Reported hazard ratio (HR) with 95% CI from each study were used as the primary outcome measure. RESULTS: Three RCTs were detected on chemotherapy with or without cetuximab regimens for AGC. Chemotherapy plus cetuximab was not significantly advantageous over chemotherapy alone for OS rate and DCR odds ratio (OR) (OS: OR=0.89, 95% CI=0.50-1.56; DCR:OR=1.11, 95% CI=0.78-1.59). However, haematological toxicity and neutropenia were lower in the experimental group (chemotherapy plus cetuximab) than in the control group (chemotherapy alone) (OR=0.65, 95% CI=0.50-0.84). No evidence of publication bias was found in this study. CONCLUSION: Adding cetuximab to chemotherapy does not improve OS or DCR compared with chemotherapy alone. Cetuximab-containing combination chemotherapy can reduce the risk of neutropenia.


Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Cetuximab/therapeutic use , Stomach Neoplasms/drug therapy , Antineoplastic Agents, Immunological/pharmacology , Cetuximab/pharmacology , Humans
17.
Cancer ; 121(12): 2044-52, 2015 Jun 15.
Article in English | MEDLINE | ID: mdl-25740697

ABSTRACT

BACKGROUND: PIWI-interacting RNAs (piRNAs), which are a novel type of identified small noncoding RNA (ncRNA), play a crucial role in germline development and carcinogenesis. METHODS: By systematically screening all known piRNAs, the authors identified 7 common single nucleotide polymorphisms (SNPs) in 9 piRNAs. Associations between these selected SNPs and the risk of colorectal cancer (CRC) were detected in a case-control study. A quantitative real-time polymerase chain reaction assay was used to evaluate messenger RNA (mRNA) expression levels of piR-015551 and of the long ncRNA (lncRNA) LNC00964-3 in 88 pairs of tissue samples. RESULTS: The assay revealed that reference SNP rs11776042 in piR-015551 was significantly associated with a decreased risk of CRC in an additive model (P = .020). However, this protective effect was not significant after correction for multiple comparisons (test for the false discovery rate; P = .140). Furthermore, the authors observed that mRNA expression levels of LNC00964-3 (an lncRNA that included the piR-015551 sequence but not piR-015551) were significantly lower in CRC tissues than in corresponding normal tissues (P = 1.5 × 10(-5) for LNC00964-3; P = .899 for piR-015551). Correlation analysis revealed that piR-015551 expression was positively correlated with expression levels of LNC00964-3 (CRC tissues: r = 0.574, P = 5.13 × 10(-9) ; normal tissues: r = 0.601, P = 5.76 × 10(-10)). Moreover, rs11776042 was not significantly correlated with mRNA expression levels of piR-015551 or LNC00964-3 (all P > .05). CONCLUSIONS: The current findings reveal the possibility that piR-015551 may be generated from LNC00964-3, which may be involved in the development of CRC.


Subject(s)
Colorectal Neoplasms/genetics , RNA, Long Noncoding/genetics , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Case-Control Studies , Colorectal Neoplasms/metabolism , Female , Genetic Predisposition to Disease , Humans , Male , Polymorphism, Single Nucleotide , RNA, Long Noncoding/metabolism
18.
Crit Rev Microbiol ; 41(2): 201-7, 2015 Jun.
Article in English | MEDLINE | ID: mdl-23919297

ABSTRACT

Human enteroviruses (HEV), very common and important human pathogens, cause infections in diverse ways. Recently, the large epidemic of HFMD caused by HEV infection became a growing threat to public health in China. As the first line of immune response, the type I interferon (IFN-α/ß) pathway plays an essential role in antiviral infection, particularly in limiting both the early and late stages of infection. Because of co-evolution with the host, the viruses have evolved multiple strategies to evade or subvert the host immunity to ensure their survival. In this paper, we systematically reviewed and summarized the interaction between HEV infections and host type I IFN responses. We firstly described the recent findings of HEV recognition and IFN induction, specifically on host pattern-recognition receptors (PRRs) in HEV infection. Then we discussed the antiviral effect of IFN in HEV infection. Finally, we timely summarized the mechanisms of HEV to circumvent the IFN responses. Clarification of the complexity in this battle may provide us new strategies for prevention and antiviral treatment.


Subject(s)
Enterovirus Infections/immunology , Enterovirus/immunology , Interferon Type I/metabolism , Signal Transduction , Enterovirus Infections/epidemiology , Host-Pathogen Interactions , Humans , Immune Evasion , Immunity, Innate
19.
Mutagenesis ; 30(2): 303-10, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25432874

ABSTRACT

Long non-coding RNA HOX transcript antisenseRNA (HOTAIR) has been widely identified to participate in tumour pathogenesis, acting as a promoter in colorectal cancer carcinogenesis. However, the association between genetic variants in HOTAIR and cancer risk has not yet been reported. In the present study, we performed a two-stage case-control study to investigate the association between HOTAIR tagSNPs and the risk of colorectal cancer. We found that individuals with rs7958904 CC genotype had a significantly decreased risk of colorectal cancer in both Stage 1 and 2, compared with those carrying GG genotype [odds ratio (OR) = 0.70, 95% confidence interval (CI) = 0.51-0.97 in Stage 1; OR = 0.58, 95% CI = 0.37-0.91 in Stage 2; OR = 0.67, 95% CI = 0.51-0.87 in combined stage]. The subsequently stratified analyses showed that the protective effect of rs7958904 was more pronounced in several subgroups. In summary, our study showed that genetic variants in HOTAIR were associated with risk of colorectal cancer and rs7958904 may act as a potential biomarker for predicting the risk of colorectal cancer.


Subject(s)
Colorectal Neoplasms/genetics , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , RNA, Long Noncoding/genetics , Adult , Aged , Case-Control Studies , Colorectal Neoplasms/epidemiology , Female , Haplotypes , Humans , Male , Middle Aged , Odds Ratio , Risk
20.
J Gastroenterol Hepatol ; 30(4): 689-95, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25302443

ABSTRACT

BACKGROUND AND AIM: Single nucleotide polymorphisms (SNPs) located in long noncoding RNA CASC8 gene may influence the process of splicing and stability of messenger RNA conformation, resulting in the modification of its interacting partners. Genome-wide association studies have identified the SNP rs10505477 and SNP rs1562430 in CASC8 were associated with risk of the colorectal cancer (CRC) and breast cancer, respectively. METHODS: In the present study, we genotyped the 940 surgically resected gastric cancer patients to explore the association between these two SNPs (e.g., rs10505477 and rs1562430) and survival of gastric cancer in a Chinese population. RESULTS: We found that the patients carrying rs10505477 GG genotype survived for a longer time than those with the GA and AA genotypes (log-rank P = 0.030). The similar result was also found in the dominant model (GA/AA vs GG, HR = 1.32, 95% CI = 1.08-1.63, log-rank P = 0.008). This risk effect was more pronounced among patients with tumor size ≤ 5 cm, diffuse-type gastric cancer, lymph node metastasis, no distant metastasis, and TNM stage III and IV. Furthermore, the area under the curve at five years was dramatically increased from 0.619 to 0.624 after adding the rs10505477 risk score to the traditional clinical risk score (TNM stage and lymph node metastasis). However, there was no association be found between the rs1562430 and the survival of gastric cancer. CONCLUSION: These findings suggested the SNP rs10505477 may contribute to the survival of gastric cancer and be a potential prognostic biomarker of gastric cancer.


Subject(s)
Asian People/genetics , Chromosomes, Human, Pair 8/genetics , Genome-Wide Association Study , Polymorphism, Single Nucleotide/genetics , RNA, Long Noncoding/genetics , Stomach Neoplasms/genetics , Humans , Lymphatic Metastasis , Neoplasm Staging , Prognosis , RNA Splicing/genetics , RNA Stability/genetics , RNA, Messenger/genetics , Risk , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Survival Rate
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