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1.
Brief Bioinform ; 24(1)2023 01 19.
Article in English | MEDLINE | ID: mdl-36572651

ABSTRACT

Immune checkpoint inhibitors (ICI) show high efficiency in a small fraction of advanced gastric cancer (GC). However, personalized immune subtypes have not been developed for the prediction of ICI efficiency in GC. Herein, we identified Pan-Immune Activation Module (PIAM), a curated gene expression profile (GEP) representing the co-infiltration of multiple immune cell types in tumor microenvironment of GC, which was associated with high expression of immunosuppressive molecules such as PD-1 and CTLA-4. We also identified Pan-Immune Dysfunction Genes (PIDG), a conservative PIAM-derivated GEP indicating the dysfunction of immune cell cooperation, which was associated with upregulation of metastatic programs (extracellular matrix receptor interaction, TGF-ß signaling, epithelial-mesenchymal transition and calcium signaling) but downregulation of proliferative signalings (MYC targets, E2F targets, mTORC1 signaling, and DNA replication and repair). Moreover, we developed 'GSClassifier', an ensemble toolkit based on top scoring pairs and extreme gradient boosting, for population-based modeling and personalized identification of GEP subtypes. With PIAM and PIDG, we developed four Pan-immune Activation and Dysfunction (PAD) subtypes and a GSClassifier model 'PAD for individual' with high accuracy in predicting response to pembrolizumab (anti-PD-1) in advance GC (AUC = 0.833). Intriguingly, PAD-II (PIAMhighPIDGlow) displayed the highest objective response rate (60.0%) compared with other subtypes (PAD-I, PIAMhighPIDGhigh, 0%; PAD-III, PIAMlowPIDGhigh, 0%; PAD-IV, PIAMlowPIDGlow, 17.6%; P = 0.003), which was further validated in the metastatic urothelial cancer cohort treated with atezolizumab (anti-PD-L1) (P = 0.018). In all, we provided 'GSClassifier' as a refined computational framework for GEP-based stratification and PAD subtypes as a promising strategy for exploring ICI responders in GC. Metastatic pathways could be potential targets for GC patients with high immune infiltration but resistance to ICI therapy.


Subject(s)
Stomach Neoplasms , Humans , Stomach Neoplasms/drug therapy , Stomach Neoplasms/genetics , Machine Learning , Tumor Microenvironment
2.
Oncogene ; 41(41): 4591-4605, 2022 10.
Article in English | MEDLINE | ID: mdl-36068334

ABSTRACT

Deciphering the crosstalk between RNA-binding proteins and corresponding RNAs will provide a better understanding of gastric cancer (GC) progression. The comprehensive bioinformatics study identified cytoplasmic polyadenylation element-binding protein 3 (CPEB3) might play a vital role in GC progression. Then we found CPEB3 was downregulated in GC and correlated with prognosis. In addition, CPEB3 suppressed GC cell proliferation, invasion and migration in vitro, as well as tumor growth and metastasis in vivo. Mechanistic study demonstrated CPEB3 interacted with 3'-UTR of ADAR1 mRNA through binding to CPEC nucleotide element, and then inhibited its translation by localizing it to processing bodies (P bodies), eventually leading to the suppression of ADAR1-mediated RNA editing. Microscale thermophoresis assay further revealed that the direct interaction between CPEB3 and GW182, the P-body's major component, was through the 440-698AA region of CPEB3 binding to the 403-860AA region of GW182. Finally, AAV9-CPEB3 was developed and administrated in mouse models to assess its potential value in gene therapy. We found AAV9-CPEB3 inhibited GC growth and metastasis. Besides, AAV9-CPEB3 induced hydropic degeneration in mouse liver, but did not cause kidney damage. These findings concluded that CPEB3 suppresses GC progression by inhibiting ADAR1-mediated RNA editing via localizing ADAR1 mRNA to P bodies.


Subject(s)
RNA Editing , Stomach Neoplasms , 3' Untranslated Regions/genetics , Adenosine Deaminase/genetics , Adenosine Deaminase/metabolism , Animals , Mice , Nucleotides , RNA Editing/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology
3.
Neoplasma ; 69(4): 886-898, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35603954

ABSTRACT

Tertiary lymphoid structures (TLS) are lymphoid aggregates in tumor tissues and their potential significance in clinical applications has not been fully elucidated in gastric cancer. We evaluated TLS and tumor-infiltrating immune cells using H&E and immunohistochemistry staining in the recruited patients with gastric cancer. The prognostic value of TLS was evaluated by Kaplan-Meier analysis and further validated using gene expression profiling. The alterations in gene mutation, copy number variance, and DNA methylation across the TLS signature subtypes were analyzed based on the Cancer Genome Atlas cohort. High TLS density was associated with improved overall survival and disease-free survival. A combination of TLS density and TNM stage obtained higher prognostic accuracy than the TNM stage alone. Tumors with high TLS density showed significantly higher infiltration of CD3+, CD8+, and CD20+ cells but lower infiltration of CD68+ cells. Transcriptomics analysis demonstrated that high TLS signature status was positively associated with the activation of inflammation-related and immune-related pathways. Multi-omics data showed a distinct landscape of somatic mutations, copy number variants, and DNA methylation across TLS signature subtypes. Our results indicated that TLS might link with enhanced immune responses, and represent an independent and beneficial predictor of resected gastric cancer. Multi-omics analysis further revealed key tumor-associated molecular alterations across TLS signature subtypes, which might help explore the potential mechanism of the interaction between TLS formation and cancer cells.


Subject(s)
Stomach Neoplasms , Tertiary Lymphoid Structures , Disease-Free Survival , Humans , Lymphocytes, Tumor-Infiltrating , Prognosis , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Tertiary Lymphoid Structures/genetics , Tertiary Lymphoid Structures/pathology , Tumor Microenvironment
4.
J Cancer ; 12(11): 3307-3314, 2021.
Article in English | MEDLINE | ID: mdl-33976740

ABSTRACT

Purpose: The effects of multidisciplinary team discussion intervention on the treatment and prognosis of advanced colorectal cancer are still controversial. Large sample size studies to evaluate the efficacy in patients with advanced colorectal cancer are lacking. Materials and Methods: We statistically analyzed the data of surgical patients diagnosed with advanced colorectal cancer from 2008 to 2014 by retrospective analysis. Patients were divided into two groups according to whether or not they received multidisciplinary team discussion intervention. After at least 3 years of follow up, differences between two groups were compared with respect to treatment process and patient prognosis. Results: The time to treatment in intervention group was shorter (9.6 ± 4.2 days vs 10.7 ± 5.6 days; p= 0.002). There were no significant differences in recurrence and metastasis rate between the two groups. Multivariate survival analysis suggested that multidisciplinary team discussion intervention reduced the risk of death (HR = 0.677; p = 0.006). And it had significant interaction with tumor invasion and tumor stage, and especially had beneficial effects in the tumor stage IV subgroup (p=0.005) and tumor invasion T4 subgroup (p<0.001). Conclusion: Multidisciplinary team discussion intervention accelerated the treatment process and reduced the death risk of patients with advanced colorectal cancer, especially improved the overall survival of stage IV and invasion T4 patients. The clinical characteristics of tumor invasion and tumor stage must be the primary considerations when judging whether patients need to conduct multidisciplinary team discussions.

5.
BMC Cancer ; 21(1): 532, 2021 May 10.
Article in English | MEDLINE | ID: mdl-33971833

ABSTRACT

BACKGROUND: The clinical staging systems for adenocarcinoma of the esophagogastric junction (AEG) are controversial. We aimed to propose a prognostic nomogram based on real-world data for predicting survival of Siewert type II/III AEG patients after surgery. METHODS: A total of 396 patients with Siewert type II/III AEG diagnosed and treated at the Center for Gastrointestinal Surgery, the First Affiliated Hospital, Sun Yat-sen University, from June 2009 to June 2017 were enrolled. The original data of 29 variables were exported from the electronic medical records system. The nomogram was established based on multivariate Cox regression coefficients, and its performance was measured using Harrell's concordance index (C-index), receiver operating characteristic (ROC) curve analysis and calibration curve. RESULTS: A nomogram was constructed based on nine variables. The C-index for overall survival (OS) prediction was 0.76 (95% CI, 0.72 to 0.80) in the training cohort, in the validation-1 cohort was 0.79 (95% CI, 0.72 to 0.86), and 0.73 (95% CI, 0.67 to 0.80) in the validation-2 cohort. Time-dependent ROC curves and calibration curves in all three cohorts showed good prognostic predictive accuracy. We further proved the superiority of the nomogram in predictive accuracy for OS to pathological TNM (pTNM) staging system and other independent prognostic factors. Kaplan-Meier survival curves demonstrated the pTNM stage, grade of differentiation, positive lymph node, log odds of positive lymph node and organ invasion were prognostic factors with good discriminative ability. CONCLUSION: The established nomogram demonstrated a more precise prognostic prediction for patients with Siewert type II/III AEG.


Subject(s)
Adenocarcinoma/mortality , Esophageal Neoplasms/mortality , Esophagogastric Junction , Nomograms , Stomach Neoplasms/mortality , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Esophageal Neoplasms/pathology , Female , Humans , Male , Middle Aged , Neoplasm Staging , Prognosis , Stomach Neoplasms/pathology
6.
Clin Res Hepatol Gastroenterol ; 41(5): 592-601, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28291626

ABSTRACT

PURPOSE: The inhibition of Mus81, a critical DNA repair gene, is recently related to the chemosensitivity of several human cancer cells such as hepatocellular carcinoma (HCC) cells. However, the role of Mus81 knockdown in chemotherapy response of colon cancer cells remains largely unknown. METHODS AND MATERIALS: The effects of Mus81 knockdown by lentivirus-mediated short hairpin RNA in sensitivity of HCT116 and LS180 colon cancer cell lines to four therapeutic drugs, including cisplatin (CDDP), were evaluated by MTT assay as well as a mouse model. Apoptosis and cell cycle distribution of HCT116 cell line was detected by flow cytometric analysis. Western blot was also employed to determine the expression of CHK1 pathway and apoptosis-related proteins in HCT116 cells and the xenograft mouse tumors. RESULTS: Mus81 knockdown could significantly improve the chemosensitivity of colon cancer cells in vitro and in vivo, especially to CDDP. Mus81 knockdown also induced S phase arrest and elevated apoptosis in CDDP treated HCT116 cells through activating CHK1/CDC25A/CDK2 and CHK1/p53/Bax pathways, while these effects could be counteracted by CHK1 inhibition. CONCLUSION: Mus81 knockdown improves the chemosensitivity of colon cancer cells by inducing S phase arrest and promoting apoptosis through activating CHK1 pathway.


Subject(s)
Checkpoint Kinase 1/physiology , Colonic Neoplasms/drug therapy , Colonic Neoplasms/genetics , DNA-Binding Proteins/genetics , Endonucleases/genetics , Cell Line, Tumor , Gene Knockdown Techniques , Humans , Signal Transduction , Tumor Cells, Cultured
7.
Cancer Lett ; 388: 177-186, 2017 03 01.
Article in English | MEDLINE | ID: mdl-27939696

ABSTRACT

Methyl methansulfonate and UV sensitive gene clone 81 (Mus81) is a critical DNA repair gene that has been implicated in development of several cancers including hepatocellular carcinoma (HCC). However, whether Mus81 can affect proliferation and survival of HCC remains unknown. In the present study, we demonstrated that the knockdown of Mus81 was associated with suppressed proliferation and elevated apoptosis of HCC cells in vitro and in vivo. Multilayered screenings, including DNA microarray, high content screen, and real-time PCR validation, identified STC2 as a proliferation-facilitating gene significantly down-regulated in HCC cells upon Mus81 knockdown. STC2 expression was also closely correlated to Mus81 expression in HCC tissues. More importantly, the restoration of STC2 expression recovered the compromised cell proliferation and survival in Mus81 depleted HCC cells. Furthermore, Mus81 knockdown was associated with the activation of APAF1, APC, and PTEN pathways and concurrent inhibition of MAPK pathway through decreasing STC2 expression. In conclusion, Mus81 knockdown suppresses proliferation and survival of HCC cells likely by downregulating STC2 expression, implicating Mus81 as a therapeutic target for HCC.


Subject(s)
Glycoproteins/genetics , Intercellular Signaling Peptides and Proteins/genetics , Animals , Apoptosis , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Cell Proliferation , Humans , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Mice , Mice, Nude , Signal Transduction , Survival Analysis
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