BackgroundLong non-coding RNAs (lncRNAs) are known to play important roles in different cell contexts, including cancers. However, little is known about lncRNAs in cholangiocarcinoma (CCA), a cholangiocyte malignancy with poor prognosis, associated with chronic inflammation and damage to the biliary epithelium. The aim of the study is to identify if any lncRNA might associate with inflammation or oxidative stress in CCA and regulate the disease progression.MethodsIn this study, RNA-seqs datasets were used to identify aberrantly expressed lncRNAs. Small interfering RNA and overexpressed plasmids were used to modulate the expression of lncRNAs, and luciferase target assay RNA immunoprecipitation (RIP) was performed to explore the mechanism of miRNA-lncRNA sponging.ResultsWe firstly analyzed five available RNA-seqs datasets to investigate aberrantly expressed lncRNAs which might associate with inflammation or oxidative stress. We identified that two lncRNAs, H19 and HULC, were differentially expressed among all the samples under the treatment of hypoxic or inflammatory factors, and they were shown to be stimulated by short-term oxidative stress responses to H2O2 and glucose oxidase in CCA cell lines. Further studies revealed that these two lncRNAs promoted cholangiocyte migration and invasion via the inflammation pathway. H19 and HULC functioned as competing endogenous RNAs (ceRNAs) by sponging let-7a/let-7b and miR-372/miR-373, respectively, which activate pivotal inflammation cytokine IL-6 and chemokine receptor CXCR4.ConclusionsOur study revealed that H19 and HULC, up-regulated by oxidative stress, regulate CCA cell migration and invasion by targeting IL-6 and CXCR4 via ceRNA patterns of sponging let-7a/let-7b and miR-372/miR-373, respectively. The results suggest that these lncRNAs might be the chief culprits of CCA pathogenesis and progression. The study provides new insight into the mechanism linking lncRNA function with CCA and may serve as novel targets for the development of new countermeasures of CCA.

Additional file 1: Figure S1. of LncRNAs H19 and HULC, activated by oxidative stress, promote cell migration and invasion in cholangiocarcinoma through a ceRNA manner

Immunotherapy, represented by immune checkpoint inhibitors (ICI), is transforming the treatment of cancer. However, only a small percentage of patients show response to ICI and there is an unmet need for biomarkers that will identify patients who are more likely to respond to immunotherapy. The fundamental basis for ICI response is the immunogenicity of a tumor, which is primarily determined by tumor antigenicity and antigen presentation efficiency. Here, we propose a method to measure tumor immunogenicity score (TIGS), which combines tumor mutational burden (TMB) and an expression signature of the antigen processing and presenting machinery (APM). In both correlation with pan-cancer ICI objective response rates (ORR) and ICI clinical response prediction for individual patients, TIGS consistently showed improved performance compared to TMB and other known prediction biomarkers for ICI response. This study suggests that TIGS is an effective tumor inherent biomarker for ICI-response prediction.

Antigen presentation and tumor immunogenicity in cancer immunotherapy response prediction

Long noncoding RNAs (lncRNAs) are recently implicated in modifying immunology in colorectal cancer (CRC). Nevertheless, the clinical significance of immune-related lncRNAs remains largely unexplored. In this study, we develope a machine learning-based integrative procedure for constructing a consensus immune-related lncRNA signature (IRLS). IRLS is an independent risk factor for overall survival and displays stable and powerful performance, but only demonstrates limited predictive value for relapse-free survival. Additionally, IRLS possesses distinctly superior accuracy than traditional clinical variables, molecular features, and 109 published signatures. Besides, the high-risk group is sensitive to fluorouracil-based adjuvant chemotherapy, while the low-risk group benefits more from bevacizumab. Notably, the low-risk group displays abundant lymphocyte infiltration, high expression of CD8A and PD-L1, and a response to pembrolizumab. Taken together, IRLS could serve as a robust and promising tool to improve clinical outcomes for individual CRC patients. 

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Machine learning-based integration develops an immune-derived lncRNA signature for improving outcomes in colorectal cancer

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Since online publication of this article, the authors noticed that an incorrect image was used during the compilation of Fig. 2a, which was caused during manuscript preparation. The correct Fig. 2a is shown below.

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Exosomal miR-25-3p from mesenchymal stem cells alleviates myocardial infarction by targeting pro-apoptotic proteins and EZH2.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics. hepatocellular carcinoma (HCC).1 Nonetheless, pseudogenes related to tumour immune infiltration and their value in improving clinical outcomes remain largely

Implications of pseudogenes for the prognosis of hepatocellular carcinoma

Hypoxia and angiogenesis are the leading causes of tumor progression, and their strong correlation has been discovered in many cancers. However, their collective function's prognostic and biological roles were not reported in gastric cancer. Hence, we aimed to investigate the effects of hypoxia and angiogenesis on gastric cancer via sequencing data. This study used weighted gene coexpression network analysis and random forest regression to build a hypoxia-angiogenesis-related model (HARM) via the TCGA-STAD lncRNA data. It estimated the HARM's correlation with clinical features and its accuracy for survival prediction. Sequential functional analyses were conducted to investigate its biological role, and we next sought the immune landscape status and immunological function variation by ESTIMATE score calculation and GSVA, respectively. Seven different algorithms were conducted to assess the immunocyte infiltration, and TIDE score and immune checkpoint levels were compared between the high- and low-HARM groups. As a result, we found that HARM predicted patient survival with high accuracy and was correlated with higher stages of gastric cancer. Various cancer-associated pathways and macrophage-related regulations were upregulated in the high-HRAM group. The high-HARM group harbored higher immune levels, and M2 macrophages and cancer-associated fibroblasts were particularly highly unfiltered. Furthermore, globally upregulated immune checkpoints and higher TIDE scores were observed in the high-HARM group. Finally, we filtered eight drugs with lower IC50 in the high-HARM group as potential drugs for the HARM-targeted therapy. We believe this study opens up novel perspectives into the interaction between hypoxia-angiogenesis and immunosuppression and will provide novel insights for gastric cancer immunotherapy.

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Identification of a Hypoxia-Angiogenesis lncRNA Signature Participating in Immunosuppression in Gastric Cancer

Genome-scale CRISPR-Cas9 screening stratifies pancreatic cancer with distinct outcomes and immunotherapeutic efficacy.

Corrigendum to "125I seeds inhibit proliferation and promote apoptosis in cholangiocarcinoma cells by regulating the AGR2-mediated p38 MAPK pathway" [Canc. Lett. 524 (2022) 29-41].

Abstract Background PI3K pathway is the most frequently mutated pathway in head and neck squamous cell carcinoma (HNSC), which plays a crucial role in tumorigenesis and progression. In the present study, we aimed to investigate the role of PI3K pathway mutation in clinical prognosis prediction and the relationship with immune microenvironment and response rate to immunotherapy. Methods We collected 129 samples with immunotherapy information from MSKCC-2019 cohort as well as 501 and 40 samples from TCGA-HNSC and MD-Anderson non-immunotherapy cohorts, respectively. Somatic mutation data was utilized to characterize the mutational status of the PI3K pathway. Subsequently, we further analyzed the differences in prognosis, immunotherapy response, genomic alterations, functional characteristics, and immune microenvironment between the mutation and wild groups. Results The Kaplan-Meier survival curves displayed that PI3K pathway mutation predicted observably prolonged overall survival (OS) in the immunotherapy cohort MSKCC-2019 ( p = 0.012) but did not reach statistical significance in the non-immunotherapy cohorts TCGA-HNSC ( p = 0.68) and MD-Anderson ( p = 0.68). After incorporating several clinicopathologic features such as age, gender, and tumor mutation burden (TMB), the results of multivariate Cox regression analysis also demonstrated that the PI3K pathway mutation could indicate better immunotherapy outcomes in HNSC patients with a hazard ratio (HR) of 0.533 (95% CI: 0.313–0.910; p = 0.021) in the immunotherapy cohort MSKCC-2019, compared with 0.888 (95% CI: 0.636–1.241; p = 0.487) and 1.939 (95% CI: 0.483–7.781; p = 0.351) in the non-immunotherapy cohorts TCGA-HNSC and MD-Anderson. In addition, the results of the subclass mapping (SubMap) and the tumor immune dysfunction and exclusion (TIDE) also consistently suggested that patients in the mutation group are more likely to benefit from immunotherapy. And further studies showed that the mutation group owned significantly higher TMB, activated immune-related pathways, richer abundance of immune cells, and higher expression levels of immunomodulators. To improve the prognosis of the wild group, we identified five relatively sensitive potential drugs for the wild group, including “BMS-536924,” “linsitinib,” “NVP-TAE684,” “PLX-4720,” and “clonazepam.” Conclusions The PI3K pathway mutation status could be considered as a potential biomarker to predict better immunotherapeutic efficacy and clinical outcomes after immunotherapy in HNSC patients. 

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Zaoqu Liu

Papers

Implications of pseudogenes for the prognosis of hepatocellular carcinoma

Identification of a Hypoxia-Angiogenesis lncRNA Signature Participating in Immunosuppression in Gastric Cancer

Genome-scale CRISPR-Cas9 screening stratifies pancreatic cancer with distinct outcomes and immunotherapeutic efficacy.

Corrigendum to "125I seeds inhibit proliferation and promote apoptosis in cholangiocarcinoma cells by regulating the AGR2-mediated p38 MAPK pathway" [Canc. Lett. 524 (2022) 29-41].

PI3K pathway mutation predicts an activated immune microenvironment and better immunotherapeutic efficacy in head and neck squamous cell carcinoma