Abstract Many types of human cells self-destruct to maintain biological homeostasis and defend the body against pathogenic substances. This process, called regulated cell death (RCD), is important for various biological activities, including the clearance of aberrant cells. Thus, RCD pathways represented by apoptosis have increased in importance as a target for the development of cancer medications in recent years. However, because tumor cells show avoidance to apoptosis, which causes treatment resistance and recurrence, numerous studies have been devoted to alternative cancer cell mortality processes, namely necroptosis, pyroptosis, ferroptosis, and cuproptosis; these RCD modalities have been extensively studied and shown to be crucial to cancer therapy effectiveness. Furthermore, evidence suggests that tumor cells undergoing regulated death may alter the immunogenicity of the tumor microenvironment (TME) to some extent, rendering it more suitable for inhibiting cancer progression and metastasis. In addition, other types of cells and components in the TME undergo the abovementioned forms of death and induce immune attacks on tumor cells, resulting in enhanced antitumor responses. Hence, this review discusses the molecular processes and features of necroptosis, pyroptosis, ferroptosis, and cuproptosis and the effects of these novel RCD modalities on tumor cell proliferation and cancer metastasis. Importantly, it introduces the complex effects of novel forms of tumor cell death on the TME and the regulated death of other cells in the TME that affect tumor biology. It also summarizes the potential agents and nanoparticles that induce or inhibit novel RCD pathways and their therapeutic effects on cancer based on evidence from in vivo and in vitro studies and reports clinical trials in which RCD inducers have been evaluated as treatments for cancer patients. Lastly, we also summarized the impact of modulating the RCD processes on cancer drug resistance and the advantages of adding RCD modulators to cancer treatment over conventional treatments. 

/pdf/targeting-cell-death-pathways-for-cancer-therapy-recent-1s2ymajs.pdf

Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research

Circular RNAs (circRNAs) are classified as noncoding RNAs because they are devoid of a 5' end cap and a 3' end poly (A) tail necessary for cap-dependent translation. However, increasing numbers of translated circRNAs identified through high-throughput RNA sequencing overlapping with polysome profiling indicate that this rule is being broken. CircRNAs can be translated in cap-independent mechanism, including IRES (internal ribosome entry site)-initiated pattern, MIRES (m6A internal ribosome entry site) -initiated patterns, and rolling translation mechanism (RCA). CircRNA-encoded proteins harbour diverse functions similar to or different from host proteins. In addition, they are linked to the modulation of human disease including carcinomas and noncarcinomas. CircRNA-related translatomics and proteomics have attracted increasing attention. This review discusses the progress and exclusive characteristics of circRNA translation and highlights the latest mechanisms and regulation of circRNA translatomics. Furthermore, we summarize the extensive functions and mechanisms of circRNA-derived proteins in human diseases, which contribute to a better understanding of intricate noncanonical circRNA translatomics and proteomics and their therapeutic potential in human diseases. 

/pdf/expanding-uncapped-translation-and-emerging-function-of-1v79wm43.pdf

Expanding uncapped translation and emerging function of circular RNA in carcinomas and noncarcinomas

/pdf/expanding-uncapped-translation-and-emerging-function-of-17frlo26.pdf

Musculoskeletal degenerative diseases (MSDDs) are pathological conditions that affect muscle, bone, cartilage, joint and connective tissue, leading to physical and functional impairments in patients, mainly consist of osteoarthritis (OA), intervertebral disc degeneration (IDD), rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) are novel regulators of gene expression that play an important role in biological regulation, involving in chondrocyte proliferation and apoptosis, extracellular matrix degradation and peripheral blood mononuclear cell inflammation. Research on MSDD pathogenesis, especially on RA and AS, is still in its infancy and major knowledge gaps remain to be filled. The effects of lncRNA/circRNA-miRNA-mRNA axis on MSDD progression help us to fully understand their contribution to the dynamic cellular processes, provide the potential OA, IDD, RA and AS therapeutic strategies. Further studies are needed to explore the mutual regulatory mechanisms between lncRNA/circRNA regulation and effective therapeutic interventions in the pathology of MSDD.

/pdf/interactions-among-lncrna-circrna-mirna-and-mrna-in-2f1va9ki9o.pdf

Interactions Among lncRNA/circRNA, miRNA, and mRNA in Musculoskeletal Degenerative Diseases.

Abstract Recent studies have identified that N 6 -methyladenosine (m 6 A) extensively participates in the myocardial injury pathophysiological process. However, the role of m 6 A on sepsis-induced myocardial injury is still unclear. Here, we investigated the functions and mechanism of m 6 A methyltransferase METTL3 for septic myocardial injury. Results illustrated that the m 6 A modification level and METTL3 up-regulated in the lipopolysaccharide (LPS)-induced cardiomyocytes (H9C2 cells). Methylated RNA immunoprecipitation sequencing (MeRIP-Seq) revealed the m 6 A profile of the septic myocardial injury cellular model. Functionally, METTL3 knockdown repressed the inflammatory damage of cardiomyocytes induced by LPS. Mechanistically, we found that HDAC4 had remarkable m 6 A modification sites on its 3’-UTR genome, acting as the downstream target of METTL3. Besides, m 6 A reader IGF2BP1 recognized the m 6 A modification sites on HDAC4 mRNA and enhanced its RNA stability. In conclusion, the findings illustrated a role of METTL3/IGF2BP1/m 6 A/HDAC4 axis on sepsis-induced myocardial injury, which might provide novel therapeutic strategy for septic myocardial injury. 

/pdf/n6-methyladenosine-m6a-methyltransferase-mettl3-regulates-2gjc3790.pdf

N6-methyladenosine (m6A) methyltransferase METTL3 regulates sepsis-induced myocardial injury through IGF2BP1/HDAC4 dependent manner

Circular RNAs a kind of covalently closed RNA and widely expressed in eukaryotes. CircRNAs are involved in a variety of physiological and pathological processes, but their regulatory mechanisms are not fully understood. Given the development of the RNA deep-sequencing technology and the improvement of algorithms, some CircRNAs are discovered to encode proteins through the cap-independent mechanism and participate in the important process of tumorigenesis and development. Based on an overview of CircRNAs, this paper summarizes its translation mechanism and research methods, and reviews the research progress of CircRNAs translation in the field of oncology in recent years. Moreover, this paper aims to provide new ideas for tumor diagnosis and treatment through CircRNAs translation.

/pdf/circular-rnas-cap-independent-translation-protein-and-its-19vjwymvwf.pdf

Circular RNAs' cap-independent translation protein and its roles in carcinomas.

N6-methyladenosine (m6A) is the most common epigenetic modification of eukaryotic RNA, which can participate in the growth and development of the body and a variety of physiological and disease processes by affecting the splicing, processing, localization, transport, translation, and degradation of RNA. Increasing evidence shows that non-coding RNAs, particularly microRNA, long non-coding RNA, and circular RNA, can also regulate the RNA m6A modification process by affecting the expression of m6A-related enzymes. The interaction between m6A modification and non-coding RNAs provides a new perspective for the exploration of the potential mechanism of tumor genesis and development. In this review, we summarize the potential mechanisms and effects of m6A and non-coding RNAs in gastrointestinal tract cancers.

The Interaction Between N6-Methyladenosine Modification and Non-Coding RNAs in Gastrointestinal Tract Cancers

N6-methyladenosine (m6A), N1-methyladenosine (m1A), 5-methylcytosine (m5C), and 7-methylguanosine (m7G) are the major forms of RNA methylation modifications, which are closely associated with the development of many tumors. However, the prognostic value of RNA methylation-related long non-coding RNAs (lncRNAs) in colon cancer (CC) has not been defined. This study summarised 50 m6A/m1A/m5C/m7G-related genes and downloaded 41 normal and 471 CC tumor samples with RNA-seq data and clinicopathological information from The Cancer Genome Atlas (TCGA) database. A total of 1057 RNA methylation-related lncRNAs (RMlncRNAs) were identified with Pearson correlation analysis. Twenty-three RMlncRNAs with prognostic values were screened using univariate Cox regression analysis. By consensus clustering analysis, CC patients were classified into two molecular subtypes (Cluster 1 and Cluster 2) with different clinical outcomes and immune microenvironmental infiltration characteristics. Cluster 2 was considered to be the “hot tumor” with a better prognosis, while cluster 1 was regarded as the “cold tumor” with a poorer prognosis. Subsequently, we constructed a seven-lncRNA prognostic signature using the least absolute shrinkage and selection operator (LASSO) Cox regression. In combination with other clinical traits, we found that the RNA methylation-related lncRNA prognostic signature (called the “RMlnc-score”) was an independent prognostic factor for patients with colon cancer. In addition, immune infiltration, immunotherapy response analysis, and half-maximum inhibitory concentration (IC50) showed that the low RMlnc-score group was more sensitive to immunotherapy, while the high RMlnc-score group was sensitive to more chemotherapeutic agents. In summary, the RMlnc-score we developed could be used to predict the prognosis, immunotherapy response, and drug sensitivity of CC patients, guiding more accurate, and personalized treatment regimens.

https://www.frontiersin.org/articles/10.3389/fgene.2022.870945/pdf

Identification of RNA Methylation-Related lncRNAs Signature for Predicting Hot and Cold Tumors and Prognosis in Colon Cancer

Background Necroptosis, is intimately linked to tumor development and prognosis and has been considered as a target for anticancer therapy. However, the role of necroptosis-related genes (NRGs) in colon cancer is unclear. Methods In the present study, we screened 76 NRGs from previous studies and described the landscape of transcriptomic and genetic variation of NRGs in colon cancer (CC) patient samples. Molecular subtypes of necroptosis in colon cancer were identified by clustering analysis, and these molecular subtypes were linked to patient prognosis and TME cell infiltration characteristics. Then, the NRS-score for predicting overall survival (OS) was built based on the TCGA database and validated in the GSE39582 cohort for its predictive power in CC patients. Besides, the ESTIMATE and CIBERSORT algorithms were applied to explore the relationship between NRS-score and tumor immune microenvironment. Results We identified two molecular subtypes associated with necroptosis in CC, which have diverse prognosis and immune microenvironment characteristics. Based on the differentially expressed genes between the two molecular subtypes, we further developed a necroptosis risk score signature, referred to as NRS-score. High NRS-score was associated with poor prognosis in CC through immunosuppressive microenvironment and immune escape mechanisms. The nomogram based on NRS-score showed excellent ability to predict prognosis. In addition, NRS-score presented a positive correlation with tumor mutational burden (TMB) and immune checkpoint blockade (ICB) expression and was closely correlated with multiple anticancer agent susceptibility. Conclusion This work revealed a close relationship between necroptosis and the prognosis and immune microenvironment of colon cancer. The NRS-score based on the 8-gene signature may be used to predict the sensitivity of immunotherapy and chemotherapy in colon cancer patients, and provides a foundation for future studies targeting necroptosis and its immune microenvironment.

/pdf/integrated-analysis-of-necroptosis-related-genes-for-1nbknoo4.pdf

Integrated Analysis of Necroptosis-Related Genes for Prognosis, Immune Microenvironment Infiltration, and Drug Sensitivity in Colon Cancer

Background: Recent studies highlight the carcinogenesis role of SHC-adaptor protein 1 (SHC1) in cancer initiation, development, and progression. However, its aberrant expression, diagnostic and prognostic value remain unknown in a variety of tumors. Methods: The SHC1 expression profiles were analyzed using GTEx database, TCGA database, Oncomine and CPTAC database. The survival analysis was conducted using GEPIA2, Kaplan-Meier Plotter, UALCAN, and PrognoScan. The diagnostic values of SHC1 were calculated with the “pROC” package in R software. The genetic alteration of SHC1 and mutations were analyzed using cBioPortal. TIMER2 was employed to estimate the correlations between SHC1 expression and tumor-infiltrating immune cells in the TCGA cohort. Enrichment analysis of SHC1 was conducted using the R package “clusterProfiler.” Results: SHC1 was ubiquitously highly expressed and closely associated with worse prognosis of multiple major cancer types (all p < 0.05). Further, SHC1 gene mutations were strongly linked to poor OS and DFS in SKCM (all p < 0.05). An enhanced phosphorylation level of SHC1 at the S139 site was observed in clear cell RCC. Additionally, the results revealed SHC1 expression was strongly linked to TMB, MMRs, MSI, TAMs, DNA methylation, m6A RNA methylation, tumor-associated immune infiltration, and immune checkpoints in multiple cancers (all p < 0.05). In addition, the results of the ROC analysis indicated the SHC1 exhibited strong diagnostic capability for KICH (AUC = 0.92), LIHC (AUC = 0.95), and PAAD (AUC = 0.95). Finally, enrichment analysis indicated that SHC1 may potentially involve in the regulation of numerous signaling pathways in cancer metabolism and protein phosphorylation-related functions. Conclusions: These findings highlight that SHC1 plays an important role in the tumor immune microenvironment, and SHC1 has been identified to have prognostic and diagnostic value in multiple cancers. Thus, SHC1 is a potential target for cancer immunotherapy and effective prognostic and diagnostic biomarker.

/pdf/pan-cancer-study-of-shc-adaptor-protein-1-shc1-as-a-11z3bdc3.pdf

Lian He

Papers

Circular RNAs' cap-independent translation protein and its roles in carcinomas.

The Interaction Between N6-Methyladenosine Modification and Non-Coding RNAs in Gastrointestinal Tract Cancers

Identification of RNA Methylation-Related lncRNAs Signature for Predicting Hot and Cold Tumors and Prognosis in Colon Cancer

Integrated Analysis of Necroptosis-Related Genes for Prognosis, Immune Microenvironment Infiltration, and Drug Sensitivity in Colon Cancer

Pan-Cancer Study of SHC-Adaptor Protein 1 (SHC1) as a Diagnostic, Prognostic and Immunological Biomarker in Human Cancer