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.

BACKGROUND A large number of patients with stage II/III colorectal cancer (CRC) have a high recurrence rate after radical resection. We aimed to develop a novel tool to stratify patients with different recurrence-risk for optimizing decision-making in post-operative surveillance and therapeutic regimens. METHODS We retrospectively enrolled four independent cohorts from the Gene Expression Omnibus and 66 CRC tissues from our hospital. The initial signature discovery was conducted in GSE143985 (n = 91). This was followed by independent validation of this signature in GSE17536 (n = 111), GSE29621 (n = 40), and GSE92921 (n = 59). Further experimental validation using qRT-PCR assays (n = 66) was performed to ensure the robustness and clinical feasible of this signature. RESULTS We developed a novel recurrence-related signature consisting of six genes. This signature was validated to be significantly associated with dismal recurrence-free survival in five cohorts GSE143985 (HR: 4.296 [2.612-7.065], P < 0.0001), GSE17536 (HR: 2.354 [1.662-3.334], P < 0.0001), GSE29621 (HR: 3.934 [1.622-9.539], P = 0.0024), GSE92921 (HR: 7.080 [2.011-24.924], P = 0.0023), and qPCR assays (HR: 3.654 [2.217-6.020], P < 0.0001). This signature was also proven to be an independent recurrent factor. More importantly, this signature displayed excellent discrimination and calibration in predicting the recurrence-risk at 1-5 years, with most AUCs were above 0.9, average C-index for the five cohorts was 0.8795, and near-perfect calibration. CONCLUSIONS We discovered and experimental validated a novel gene signature with stable and powerful performance for identifying patients at high recurrence-risk in stage II/III CRC.

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Development and clinical validation of a novel six-gene signature for accurately predicting the recurrence risk of patients with stage II/III colorectal cancer.

Molecular subtypes of colorectal cancer (CRC) are currently identified via the snapshot transcriptional profiles, largely ignoring the dynamic changes of gene expressions. Conversely, biological networks remain relatively stable irrespective of time and condition. Here, we introduce an individual-specific gene interaction perturbation network-based (GIN) approach and identify six GIN subtypes (GINS1-6) with distinguishing features: (i) GINS1 (proliferative, 24%∼34%), elevated proliferative activity, high tumor purity, immune-desert, PIK3CA mutations, and immunotherapeutic resistance; (ii) GINS2 (stromal-rich, 14%∼22%), abundant fibroblasts, immune-suppressed, stem-cell-like, SMAD4 mutations, unfavorable prognosis, high potential of recurrence and metastasis, immunotherapeutic resistance, and sensitive to fluorouracil-based chemotherapy; (iii) GINS3 (KRAS-inactivated, 13%∼20%), high tumor purity, immune-desert, activation of EGFR and ephrin receptors, chromosomal instability (CIN), fewer KRAS mutations, SMOC1 methylation, immunotherapeutic resistance, and sensitive to cetuximab and bevacizumab; (iv) GINS4 (mixed, 10%∼19%), moderate level of stromal and immune activities, transit-amplifying-like, and TMEM106A methylation; (v) GINS5 (immune-activated, 12%∼24%), stronger immune activation, plentiful tumor mutation and neoantigen burden, microsatellite instability and high CpG island methylator phenotype, BRAF mutations, favorable prognosis, and sensitive to immunotherapy and PARP inhibitors; (vi) GINS6, (metabolic, 5%∼8%), accumulated fatty acids, enterocyte-like, and BMP activity. Overall, the novel high-resolution taxonomy derived from an interactome perspective could facilitate more effective management of CRC patients.

https://www.biorxiv.org/content/biorxiv/early/2022/09/05/2022.09.02.506442.full.pdf

Gene interaction perturbation network deciphers a high-resolution taxonomy in colorectal cancer

Abstract Background Mounting evidence has revealed the dynamic variations in the cellular status and phenotype of the smooth muscle cell (SMC) are vital for shaping the atherosclerotic plaque microenvironment and ultimately mapping onto heterogeneous clinical outcomes in coronary artery disease. Currently, the underlying clinical significance of SMC evolutions remains unexplored in atherosclerosis. Methods The dissociated cells from diseased segments within the right coronary artery of four cardiac transplant recipients and 1070 bulk samples with atherosclerosis from six bulk cohorts were retrieved. Following the SMC fate trajectory reconstruction, the MOVICS algorithm integrating the nearest template prediction was used to develop a stable and robust molecular classification. Subsequently, multi-dimensional potential biological implications, molecular features, and cell landscape heterogeneity among distinct clusters were decoded. Results We proposed an SMC cell fate decision signature (SCFDS)-based atherosclerosis stratification system and identified three SCFDS subtypes (C1–C3) with distinguishing features: (i) C1 (DNA-damage repair type), elevated base excision repair (BER), DNA replication, as well as oxidative phosphorylation status. (ii) C2 (immune-activated type), stronger immune activation, hyper-inflammatory state, the complex as well as varied lesion microenvironment, advanced stage, the most severe degree of coronary stenosis severity. (iii) C3 (stromal-rich type), abundant fibrous content, stronger ECM metabolism, immune-suppressed microenvironment. Conclusions This study uncovered atherosclerosis complex cellular heterogeneity and a differentiated hierarchy of cell populations underlying SMC. The novel high-resolution stratification system could improve clinical outcomes and facilitate individualized management. 

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Smooth muscle cell fate decisions decipher a high-resolution heterogeneity within atherosclerosis molecular subtypes

Background Fluorouracil (FU)-based chemotherapy regimens are indispensable in the comprehensive treatment of colorectal cancer (CRC). However, the heterogeneity of treated individuals and the severe adverse effects of chemotherapy results in limited overall benefit. Methods Firstly, Weighted gene co-expression network analysis (WGCNA) identified modules tightly associated with chemotherapy response. Then, the in-house cohort and prognostic cohorts from TCGA and GEO were subjected to Cox proportional hazards model and survival analysis to ascertain the predictable function of SCG2 on the prognosis of CRC patients. Finally, we performed In vitro experiments, functional analysis, somatic mutation, and copy number variation research to explore the biological characteristics of SCG2. Results We identified red and green as the modules most associated with chemotherapy response, in which SCG2 was considered a risky factor with higher expression predicting poorer prognosis. SCG2 expression in the APC non-mutation group was remarkably higher than in the mutation group. The mutation frequencies of amplified genes differed significantly between different SCG2 expression subgroups. Besides, CRC cell lines with SCG2 knockdown have reduced invasive, proliferative, and proliferative capacity. We discovered that the SCG2 high expression subgroup was the immune hot type and considered more suitable for immunotherapy. Conclusion This study demonstrates the clinical significance and biological characteristics of SCG2, which could serve as a promising biomarker to identify patients who may benefit from chemotherapy and immunotherapy.

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SCG2: A Prognostic Marker That Pinpoints Chemotherapy and Immunotherapy in Colorectal Cancer

Abstract The incidence and mortality of cancer are the major health issue worldwide. Apart from the treatments developed to date, the unsatisfactory therapeutic effects of cancers have not been addressed by broadening the toolbox. The advent of immunotherapy has ushered in a new era in the treatments of solid tumors, but remains limited and requires breaking adverse effects. Meanwhile, the development of advanced technologies can be further boosted by gene analysis and manipulation at the molecular level. The advent of cutting-edge genome editing technology, especially clustered regularly interspaced short palindromic repeats (CRISPR-Cas9), has demonstrated its potential to break the limits of immunotherapy in cancers. In this review, the mechanism of CRISPR-Cas9-mediated genome editing and a powerful CRISPR toolbox are introduced. Furthermore, we focus on reviewing the impact of CRISPR-induced double-strand breaks (DSBs) on cancer immunotherapy (knockout or knockin). Finally, we discuss the CRISPR-Cas9-based genome-wide screening for target identification, emphasis the potential of spatial CRISPR genomics, and present the comprehensive application and challenges in basic research, translational medicine and clinics of CRISPR-Cas9. 

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Zaoqu Liu

Papers

Development and clinical validation of a novel six-gene signature for accurately predicting the recurrence risk of patients with stage II/III colorectal cancer.

Gene interaction perturbation network deciphers a high-resolution taxonomy in colorectal cancer

Smooth muscle cell fate decisions decipher a high-resolution heterogeneity within atherosclerosis molecular subtypes

SCG2: A Prognostic Marker That Pinpoints Chemotherapy and Immunotherapy in Colorectal Cancer

Recent advances and applications of CRISPR-Cas9 in cancer immunotherapy