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Endoplasmic reticulum stress regulators exhibit different prognostic, therapeutic and immune landscapes in pancreatic adenocarcinoma.

ABSTRACT: Endoplasmic reticulum stress (ERS) and unfolded protein response are the critical processes of tumour biology. However, the roles of ERS regulatory genes in pancreatic adenocarcinoma (PAAD) remain elusive. A novel ERS-related risk signature was constructed using the Lasso regression analysis. Its prognostic value, immune effect, metabolic influence, mutational feature and therapeutic correlation were comprehensively analysed through multiple bioinformatic approaches. The biofunctions of KDELR3 and YWHAZ in pancreatic cancer (PC) cells were also investigated through colony formation, Transwell assays, flow cytometric detection and a xenograft model. The upstream miRNA regulatory mechanism of KDELR3 was predicted and validated. ERS risk score was identified as an independent prognostic factor and could improve traditional prognostic model. Meanwhile, it was closely associated with metabolic reprogramming and tumour immune. High ERS risk enhanced glycolysis process and nucleotide metabolism, but was unfavourable for anti-tumour immune response. Moreover, ERS risk score could act as a potential biomarker for predicting the efficacy of ICBs. Overexpression of KDELR3 and YWHAZ stimulated the proliferation, migration and invasion of SW1990 and BxPC-3 cells. Silencing KDELR3 suppressed tumour growth in a xenograft model. miR-137 could weaken the malignant potentials of PC cells through inhibiting KDELR3 (5'-AGCAAUAA-3'). ERS risk score greatly contributed to PAAD clinical assessment. KDELR3 and YWHAZ possessed cancer-promoting capacities, showing promise as a novel treatment target.

SUBMITTER: Liu S

PROVIDER: S-EPMC10902308 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Endoplasmic reticulum stress regulators exhibit different prognostic, therapeutic and immune landscapes in pancreatic adenocarcinoma.

Liu Shanshan S He Kaini K Yang Longbao L Xu Fangshi F Cui Xiaoguang X Qu Li L Li Xueyi X Ren Bin-Cheng BC

Journal of cellular and molecular medicine 20240201 5

Endoplasmic reticulum stress (ERS) and unfolded protein response are the critical processes of tumour biology. However, the roles of ERS regulatory genes in pancreatic adenocarcinoma (PAAD) remain elusive. A novel ERS-related risk signature was constructed using the Lasso regression analysis. Its prognostic value, immune effect, metabolic influence, mutational feature and therapeutic correlation were comprehensively analysed through multiple bioinformatic approaches. The biofunctions of KDELR3 a ...[more]

PMID: 38303549

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Project description:Analysis of gene expression can be challenging, especially if it involves genetically diverse populations that exhibit high variation in their individual expression profile. Despite this variation, it is conceivable that in the same individuals a high degree of coordination is maintained between transcripts that belong to the same signaling modules and are associated with related biological functions. To explore this further, we calculated the correlation in the expression levels between each of ATF4, CHOP (DDIT3), GRP94, DNAJB9 (ERdj4), DNAJ3C (P58IPK), and HSPA5 (BiP/GRP78) with the whole transcriptome in primary fibroblasts from deer mice following induction of endoplasmic reticulum (ER) stress. Since these genes are associated with different transducers of the unfolded protein response (UPR), we postulated that their profile, in terms of correlation of transcripts, reflects distinct UPR branches engaged, and therefore different biological processes. Standard gene ontology analysis was able to predict major functions associated with the corresponding transcript, and of the UPR arm related to that, namely regulation of the apoptotic response by ATF4 (PERK arm) and the ER stress-associated degradation for GRP94 (IRE1). BiP, being a global regulator of the UPR, was associated with activation of ER stress in a rather global manner. Pairwise comparison in the correlation coefficients for these genes' associated transcriptome showed the relevance of selected genes in terms of expression profiles. Conventional assessment of differential gene expression was incapable of providing meaningful information and pointed only to a generic association with stress. Collectively, this approach suggests that by evaluating the degree of coordination in gene expression, in genetically diverse biological specimens, may be useful in assigning genes in transcriptome networks, and more importantly in linking signaling nodules to specific biological functions and processes.

Project description:Lung adenocarcinoma (LUAD) is one of the most universal types of cancer all over the world and its morbidity continues to rise year by year. Growing evidence has demonstrated that endoplasmic reticulum stress is highly activated in cancer cells and plays a key role in regulating the fate of cancer cells. However, the role and mechanism of endoplasmic reticulum stress in lung adenocarcinoma genesis and development remains unclear. In this research, we developed a prognostic model to predict the overall survival of patients with LUAD utilizing endoplasmic reticulum stress-related genes and screened out potential small molecular compounds, which could assist the clinician in making accurate decisions and better treat LUAD patients. Firstly, we downloaded 419 endoplasmic reticulum stress-related genes (ERSRGs) from Molecular Signatures Database (MSigDB). Secondly, we obtained information about the transcriptome profiling and corresponding clinical data of 59 normal samples and 535 lung adenocarcinoma samples from The Cancer Genome Atlas (TCGA) database. Next, we used the DESeq2 package to identify differentially expressed genes related to endoplasmic reticulum stress. We performed univariate Cox, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analysis to establish a prognostic model for LUAD patients based on ERSRGs. Then, we carried out univariate and multivariate independent prognostic analysis of endoplasmic reticulum stress-related gene (ERSRG) score and some clinical traits of lung adenocarcinoma. Additionally, we developed a clinically applicable nomogram for predicting survival for LUAD patients over one, three, and five years. Moreover, we carried out a drug sensitivity analysis to identify novel small molecule compounds for LUAD treatment. Finally, we examined the tumor microenvironment (TME) and immune cell infiltrating analysis to explore the interactions between immune and cancer cells. 142 differentially expressed ERSRGs were identified by using the DESeq2 package. A prognostic model was built based on 7 differentially expressed ERSRGs after performing univariate Cox regression, LASSO regression, and multivariate Cox regression analysis. According to the results of univariate and multivariate independent prognostic analysis, we found ERSRG score can be used as an independent prognostic maker. Using the Kaplan-Meier curves, we found low-risk patients had higher survival probability than high-risk patients in both training set and test set. A nomogram was drawn to predict 1-, 3-, and 5-year survival probability. The calibration curves explained good performance of the model for the prediction of survival. Phenformin, OSU-03012, GSK-650394 and KIN001-135 were identified as the drugs most likely to provide important information to clinicians about the treatment of LUAD patients. A prognostic prediction model was established based on 7 differentially expressed ERSRGs (PDX1, IGFBP1, DDIT4, PPP1R3G, CFTR, DERL3 and NUPR1), which could effectively predict the prognosis of LUAD patients and give a reference for clinical doctors to help LUAD patients to make better treatment tactics. Based on the 4 small molecule compounds (Phenformin, OSU-03012, GSK-650394 and KIN001-135) we discovered, targeting endoplasmic reticulum stress-related genes may also be a therapeutic approach for LUAD patients.

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Endoplasmic reticulum stress regulators exhibit different prognostic, therapeutic and immune landscapes in pancreatic adenocarcinoma.

Publications

Endoplasmic reticulum stress regulators exhibit different prognostic, therapeutic and immune landscapes in pancreatic adenocarcinoma.

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