Endoplasmic reticulum stress-a key guardian in cancer.

Endoplasmic reticulum stress (ERS) is a cellular stress response characterized by excessive contraction of the endoplasmic reticulum (ER). It is a pathological hallmark of many diseases, such as diabetes, obesity, and neurodegenerative diseases. In the unique growth characteristic and varied microenvironment of cancer, high levels of stress are necessary to maintain the rapid proliferation and metastasis of tumor cells. This process is closely related to ERS, which enhances the ability of tumor cells to adapt to unfavorable environments and promotes the malignant progression of cancer. In this paper, we review the roles and mechanisms of ERS in tumor cell proliferation, apoptosis, metastasis, angiogenesis, drug resistance, cellular metabolism, and immune response. We found that ERS can modulate tumor progression via the unfolded protein response (UPR) signaling of IRE1, PERK, and ATF6. Targeting the ERS may be a new strategy to attenuate the protective effects of ERS on cancer. This manuscript explores the potential of ERS-targeted therapies, detailing the mechanisms through which ERS influences cancer progression and highlighting experimental and clinical evidence supporting these strategies. Through this review, we aim to deepen our understanding of the role of ER stress in cancer development and provide new insights for cancer therapy.

Circular RNA hsa_circ_0000467 promotes colorectal cancer progression by promoting eIF4A3-mediated c-Myc translation.

BACKGROUND: Colorectal cancer (CRC) is the second most common malignant tumor worldwide, and its incidence rate increases annually. Early diagnosis and treatment are crucial for improving the prognosis of patients with colorectal cancer. Circular RNAs are noncoding RNAs with a closed-loop structure that play a significant role in tumor development. However, the role of circular RNAs in CRC is poorly understood. METHODS: The circular RNA hsa_circ_0000467 was screened in CRC circRNA microarrays using a bioinformatics analysis, and the expression of hsa_circ_0000467 in CRC tissues was determined by in situ hybridization. The associations between the expression level of hsa_circ_0000467 and the clinical characteristics of CRC patients were evaluated. Then, the role of hsa_circ_0000467 in CRC growth and metastasis was assessed by CCK8 assay, EdU assay, plate colony formation assay, wound healing assay, and Transwell assay in vitro and in a mouse model of CRC in vivo. Proteomic analysis and western blotting were performed to investigate the effect of hsa_circ_0000467 on c-Myc signaling. Polysome profiling, RT‒qPCR and dual-luciferase reporter assays were performed to determine the effect of hsa_circ_0000467 on c-Myc translation. RNA pull-down, RNA immunoprecipitation (RIP) and immunofluorescence staining were performed to assess the effect of hsa_circ_0000467 on eIF4A3 distribution. RESULTS: In this study, we found that the circular RNA hsa_circ_0000467 is highly expressed in colorectal cancer and is significantly correlated with poor prognosis in CRC patients. In vitro and in vivo experiments revealed that hsa_circ_0000467 promotes the growth and metastasis of colorectal cancer cells. Mechanistically, hsa_circ_0000467 binds eIF4A3 to suppress its nuclear translocation. In addition, it can also act as a scaffold molecule that binds eIF4A3 and c-Myc mRNA to form complexes in the cytoplasm, thereby promoting the translation of c-Myc. In turn, c-Myc upregulates its downstream targets, including the cell cycle-related factors cyclin D2 and CDK4 and the tight junction-related factor ZEB1, and downregulates E-cadherin, which ultimately promotes the growth and metastasis of CRC. CONCLUSIONS: Our findings revealed that hsa_circRNA_0000467 plays a role in the progression of CRC by promoting eIF4A3-mediated c-Myc translation. This study provides a theoretical basis and molecular target for the diagnosis and treatment of CRC.

Identification of protein methyltransferases 5 associated with ferroptosis and immune cell infiltration of head and neck squamous cell carcinoma.

Head and neck tumors are malignant tumors that appear in the head and neck. Although much progress has been made in the treatment of head and neck tumors, many challenges remain. The prognosis of some advanced cases remains poor and survival and quality of life after treatment face certain limitations. Therefore, further research into the pathogenesis and treatment options for head and neck tumors is important in order to improve the prognosis and quality of life of patients. The Protein Arginine Methyltransferase (PRMT) family is a class of enzymes that are responsible for adding methyl groups to arginine residues in proteins. PRMT family members play important roles in regulating many cellular processes, such as transcriptional regulation, signaling, and cell cycle regulation. Recent studies have shown that the PRMT family also plays an important function in tumorigenesis and development. Here, we found that PRMT family members are significantly overexpressed in head and neck tumors and that PRMT5 may serve as an independent prognostic factor in head and neck tumors. We found that PRMT5-regulated differential genes were significantly enriched in tumor-associated signaling pathways such as IL-17 and p53. And we also found that the expression of PRMT5 in head and neck tumors was significantly correlated with immune cell infiltration, m6A as well as the expression of ferroptosis-related genes, and drug sensitivity. These results suggest that PRMT may play an important role in the development of head and neck tumors.

Epstein-Barr virus suppresses N6-methyladenosine modification of TLR9 to promote immune evasion.

Epstein-Barr virus (EBV) is a human tumor virus associated with a variety of malignancies, including nasopharyngeal carcinoma, gastric cancers, and B-cell lymphomas. N6-methyladenosine (m6A) modifications modulate a wide range of cellular processes and participate in the regulation of virus-host cell interactions. Here, we discovered that EBV infection downregulates toll-like receptor 9 (TLR9) m6A modification levels and thus inhibits TLR9 expression. TLR9 has multiple m6A modification sites. Knockdown of METTL3, an m6A "writer", decreases TLR9 protein expression by inhibiting its mRNA stability. Mechanistically, Epstein-Barr nuclear antigen 1 increases METTL3 protein degradation via K48-linked ubiquitin-proteasome pathway. Additionally, YTHDF1 was identified as an m6A "reader" of TLR9, enhancing TLR9 expression by promoting mRNA translation in an m6A -dependent manner, which suggests that EBV inhibits TLR9 translation by "hijacking" host m6A modification mechanism. Using the METTL3 inhibitor STM2457 inhibits TLR9-induced B cell proliferation and immunoglobulin secretion, and opposes TLR9-induced immune responses to assist tumor cell immune escape. In clinical lymphoma samples, the expression of METTL3, YTHDF1, and TLR9 was highly correlated with immune cells infiltration. This study reveals a novel mechanism that EBV represses the important innate immunity molecule TLR9 through modulating the host m6A modification system.

Diallyl disulfide induces DNA damage and growth inhibition in colorectal cancer cells by promoting POU2F1 ubiquitination.

Previous studies have demonstrated that diallyl disulfide (DADS) exhibits potent anti-tumor activity. However, the pharmacological actions of DADS in inhibiting the growth of colorectal cancer (CRC) cells have not been clarified. Herein, we show that DADS treatment impairs the activation of the pentose phosphate pathway (PPP) to decrease PRPP (5-phosphate ribose-1-pyrophosphate) production, enhancing DNA damage and cell apoptosis, and inhibiting the growth of CRC cells. Mechanistically, DADS treatment promoted POU2F1 K48-linked ubiquitination and degradation by attenuating the PI3K/AKT signaling to up-regulate TRIM21 expression in CRC cells. Evidently, TRIM21 interacted with POU2F1, and induced the K272 ubiquitination of POU2F1. The effects of DADS on the enhanced K272 ubiquitination of POU2F1, the PPP flux, PRPP production, DNA damage and cell apoptosis as well as the growth of CRC tumors in vivo were significantly mitigated by TRIM21 silencing or activating the PI3K signaling in CRC cells. Conversely, the effects of DADS were enhanced by TRIM21 over-expression or inhibiting the PI3K/AKT signaling in CRC cells. Collectively, our findings reveal a novel mechanism by which DADS suppresses the growth of CRC by promoting POU2F1 ubiquitination, and may aid in design of novel therapeutic intervention of CRC.

Cellular metabolism: A key player in cancer ferroptosis.

Cellular metabolism is the fundamental process by which cells maintain growth and self-renewal. It produces energy, furnishes raw materials, and intermediates for biomolecule synthesis, and modulates enzyme activity to sustain normal cellular functions. Cellular metabolism is the foundation of cellular life processes and plays a regulatory role in various biological functions, including programmed cell death. Ferroptosis is a recently discovered form of iron-dependent programmed cell death. The inhibition of ferroptosis plays a crucial role in tumorigenesis and tumor progression. However, the role of cellular metabolism, particularly glucose and amino acid metabolism, in cancer ferroptosis is not well understood. Here, we reviewed glucose, lipid, amino acid, iron and selenium metabolism involvement in cancer cell ferroptosis to elucidate the impact of different metabolic pathways on this process. Additionally, we provided a detailed overview of agents used to induce cancer ferroptosis. We explained that the metabolism of tumor cells plays a crucial role in maintaining intracellular redox homeostasis and that disrupting the normal metabolic processes in these cells renders them more susceptible to iron-induced cell death, resulting in enhanced tumor cell killing. The combination of ferroptosis inducers and cellular metabolism inhibitors may be a novel approach to future cancer therapy and an important strategy to advance the development of treatments.

The roles and molecular mechanisms of non-coding RNA in cancer metabolic reprogramming.

One of the key features of cancer is energy metabolic reprogramming which is tightly related to cancer proliferation, invasion, metastasis, and chemotherapy resistance. NcRNAs are a class of RNAs having no protein-coding potential and mainly include microRNAs, lncRNAs and circRNAs. Accumulated evidence has suggested that ncRNAs play an essential role in regulating cancer metabolic reprogramming, and the altered metabolic networks mediated by ncRNAs primarily drive carcinogenesis by regulating the expression of metabolic enzymes and transporter proteins. Importantly, accumulated research has revealed that dysregulated ncRNAs mediate metabolic reprogramming contributing to the generation of therapeutic tolerance. Elucidating the molecular mechanism of ncRNAs in cancer metabolic reprogramming can provide promising metabolism-related therapeutic targets for treatment as well as overcome therapeutic tolerance. In conclusion, this review updates the latest molecular mechanisms of ncRNAs related to cancer metabolic reprogramming.

HPV E6/E7: insights into their regulatory role and mechanism in signaling pathways in HPV-associated tumor.

Human papillomavirus (HPV) is a class of envelope-free double-stranded DNA virus. HPV infection has been strongly associated with the development of many malignancies, such as cervical, anal and oral cancers. The viral oncoproteins E6 and E7 perform central roles on HPV-induced carcinogenic processes. During tumor development, it usually goes along with the activation of abnormal signaling pathways. E6 and E7 induces changes in cell cycle, proliferation, invasion, metastasis and other biological behaviors by affecting downstream tumor-related signaling pathways, thus promoting malignant transformation of cells and ultimately leading to tumorigenesis and progression. Here, we summarized that E6 and E7 proteins promote HPV-associated tumorigenesis and development by regulating the activation of various tumor-related signaling pathways, for example, the Wnt/ß-catenin, PI3K/Akt, and NF-kB signaling pathway. We also discussed the importance of HPV-encoded E6 and E7 and their regulated tumor-related signaling pathways for the diagnosis and effective treatment of HPV-associated tumors.

Ferritinophagy: research advance and clinical significance in cancers.

Ferritinophagy, a process involving selective autophagy of ferritin facilitated by nuclear receptor coactivator 4 (NCOA4), entails the recognition of ferritin by NCOA4 and subsequent delivery to the autophagosome. Within the autophagosome, ferritin undergoes degradation, leading to the release of iron in the lysosome. It is worth noting that excessive iron levels can trigger cell death. Recent evidence has elucidated the significant roles played by ferritinophagy and ferroptosis in regulation the initiation and progression of cancer. Given the crucial role of ferritinophagy in tumor biology, it may serve as a potential target for future anti-tumor therapeutic interventions. In this study, we have provided the distinctive features of ferritinophagy and its distinctions from ferroptosis. Moreover, we have briefly examined the fundamental regulatory mechanisms of ferritinophagy, encompassing the involvement of the specific receptor NCOA4, the Nrf2/HO-1 signaling and other pathways. Subsequently, we have synthesized the current understanding of the impact of ferritinophagy on cancer progression and its potential therapeutic applications, with a particular emphasis on the utilization of chemotherapy, nanomaterials, and immunotherapy to target the ferritinophagy pathway for anti-tumor purposes.

EphA2 as a phase separation protein associated with ferroptosis and immune cell infiltration in colorectal cancer.

Colorectal cancer is one of the most common malignant tumors in the digestive system, and its high incidence and metastasis rate make it a terrible killer that threatens human health. In-depth exploration of the targets affecting the progression of colorectal cancer cells and the development of specific targeted drugs for them are of great significance for the prognosis of colorectal cancer patients. Erythropoietin-producing hepatocellular A2 (EphA2) is a member of the Eph subfamily with tyrosine kinase activity, plays a key role in the regulation of signaling pathways related to the malignant phenotype of various tumor cells, but its specific regulatory mechanism in colorectal cancer needs to be further clarified. Here, we found that EphA2 was abnormally highly expressed in colorectal cancer and that patients with colorectal cancer with high EphA2 expression had a worse prognosis. We also found that EphA2 can form liquid-liquid phase separation condensates on cell membrane, which can be disrupted by ALW-II-41-27, an inhibitor of EphA2. In addition, we found that EphA2 expression in colorectal cancer was positively correlated with the expression of ferroptosis-related genes and the infiltration of multiple immune cells. These findings suggest that EphA2 is a novel membrane protein with phase separation ability and is associated with ferroptosis and immune cell infiltration, which further suggests that malignant progression of colorectal cancer may be inhibited by suppressing the phase separation ability of EphA2.

N6-methyladenosine modification-a key player in viral infection.

N6-methyladenosine (m6A) modification is a dynamic, reversible process and is the most prevalent internal modification of RNA. This modification is regulated by three protein groups: methyltransferases ("writers"), demethylases ("erasers"), and m6A-binding proteins ("readers"). m6A modification and related enzymes could represent an optimal strategy to deepen the epigenetic mechanism. Numerous reports have suggested that aberrant modifications of m6A lead to aberrant expression of important viral genes. Here, we review the role of m6A modifications in viral replication and virus-host interactions. In particular, we focus on DNA and RNA viruses associated with human diseases, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human immunodeficiency virus (HIV)-1, Epstein-Barr virus (EBV), and Kaposi's sarcoma-associated herpesvirus (KSHV). These findings will contribute to the understanding of the mechanisms of virus-host interactions and the design of future therapeutic targets for treatment of tumors associated with viral infections.

X-ray cross-complementing family: the bridge linking DNA damage repair and cancer.

Genomic instability is a common hallmark of human tumours. As a carrier of genetic information, DNA is constantly threatened by various damaging factors that, if not repaired in time, can affect the transmission of genetic information and lead to cellular carcinogenesis. In response to these threats, cells have evolved a range of DNA damage response mechanisms, including DNA damage repair, to maintain genomic stability. The X-ray repair cross-complementary gene family (XRCC) comprises an important class of DNA damage repair genes that encode proteins that play important roles in DNA single-strand breakage and DNA base damage repair. The dysfunction of the XRCC gene family is associated with the development of various tumours. In the context of tumours, mutations in XRCC and its aberrant expression, result in abnormal DNA damage repair, thus contributing to the malignant progression of tumour cells. In this review, we summarise the significant roles played by XRCC in diverse tumour types. In addition, we discuss the correlation between the XRCC family members and tumour therapeutic sensitivity.

Organoids: opportunities and challenges of cancer therapy.

Organoids are a class of multicellular structures with the capability of self-organizing and the characteristic of original tissues, they are generated from stem cells in 3D culture in vitro. Organoids can mimic the occurrence and progression of original tissues and widely used in disease models in recent years. The ability of tumor organoids to retain characteristic of original tumors make them unique for tumorigenesis and cancer therapy. However, the history of organoid development and the application of organoid technology in cancer therapy are not well understood. In this paper, we reviewed the history of organoids development, the culture methods of tumor organoids establishing and the applications of organoids in cancer research for better understanding the process of tumor development and providing better strategies for cancer therapy. The standardization of organoids cultivation facilitated the large-scale production of tumor organoids. Moreover, it was found that combination of tumor organoids and other cells such as immune cells, fibroblasts and nervous cells would better mimic the microenvironment of tumor progression. This might be important developing directions for tumor organoids in the future.

Metabolic reprogramming and epigenetic modifications in cancer: from the impacts and mechanisms to the treatment potential.

Metabolic reprogramming and epigenetic modifications are hallmarks of cancer cells. In cancer cells, metabolic pathway activity varies during tumorigenesis and cancer progression, indicating regulated metabolic plasticity. Metabolic changes are often closely related to epigenetic changes, such as alterations in the expression or activity of epigenetically modified enzymes, which may exert a direct or an indirect influence on cellular metabolism. Therefore, exploring the mechanisms underlying epigenetic modifications regulating the reprogramming of tumor cell metabolism is important for further understanding tumor pathogenesis. Here, we mainly focus on the latest studies on epigenetic modifications related to cancer cell metabolism regulations, including changes in glucose, lipid and amino acid metabolism in the cancer context, and then emphasize the mechanisms related to tumor cell epigenetic modifications. Specifically, we discuss the role played by DNA methylation, chromatin remodeling, noncoding RNAs and histone lactylation in tumor growth and progression. Finally, we summarize the prospects of potential cancer therapeutic strategies based on metabolic reprogramming and epigenetic changes in tumor cells.

The function and mechanism of lactate and lactylation in tumor metabolism and microenvironment.

Lactate is an end product of glycolysis. Owing to the lactate shuttle concept introduced in the early 1980s, increasing researchers indicate lactate as a critical energy source for mitochondrial respiration and as a precursor of gluconeogenesis. Lactate also acts as a multifunctional signaling molecule through receptors expressed in various cells, resulting in diverse biological consequences including decreased lipolysis, immune regulation, and anti-inflammation wound healing, and enhanced exercise performance in association with the gut microbiome. Furthermore, increasing evidence reveals that lactate contributes to epigenetic gene regulation by lactylating lysine residues of histones, which accounts for its key role in immune modulation and maintenance of homeostasis. Here, we summarize the function and mechanism of lactate and lactylation in tumor metabolism and microenvironment.

Exosomal cargos-mediated metabolic reprogramming in tumor microenvironment.

Metabolic reprogramming is one of the hallmarks of cancer. As nutrients are scarce in the tumor microenvironment (TME), tumor cells adopt multiple metabolic adaptations to meet their growth requirements. Metabolic reprogramming is not only present in tumor cells, but exosomal cargos mediates intercellular communication between tumor cells and non-tumor cells in the TME, inducing metabolic remodeling to create an outpost of microvascular enrichment and immune escape. Here, we highlight the composition and characteristics of TME, meanwhile summarize the components of exosomal cargos and their corresponding sorting mode. Functionally, these exosomal cargos-mediated metabolic reprogramming improves the "soil" for tumor growth and metastasis. Moreover, we discuss the abnormal tumor metabolism targeted by exosomal cargos and its potential antitumor therapy. In conclusion, this review updates the current role of exosomal cargos in TME metabolic reprogramming and enriches the future application scenarios of exosomes.

Clinical significance and integrative analysis of the cuproptosis-associated genes in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSC) is a kind of malignant tumor originating from the oropharynx, larynx, nasopharynx and oral cavity. The incidence of HNSC is increasing and it is the sixth malignant tumor in the world at present. "Cuprotosis" is a novel cuper-dependent cell death mode that is closely related to mitochondrial respiration. Tumorigenesis is closely related to the dysregulation of cell death. However, the relationship between cuprotosis and HNSC remains unclear. Here, we investigated the association between 10 cuprotosis-associated genes (CAGs) and HNSC using multi-omics public data. We found that CAGs had abnormal expression and significant genetic changes in HNSC, especially CDKN2A with 54% mutation rate. Expression of CAGs significantly correlates with the prognosis of HNSC patients. Moreover, the CAGs expression is correlated with the immune checkpoints expression and immune cells infiltration. These CAGs expression was associated with multiple drugs sensitivity of cancer cells, such as cisplatin and docetaxel. These findings indicate that CAGs are likely to serve an essential role in the diagnosis, prognosis, immunotherapy and drug therapy prediction of HNSC.

RNA helicase DDX5-induced circPHF14 promotes gastric cancer cell progression.

As a well-established member of a strongly conserved protein family, DDX5 binds to RNA helicase in a specific manner, which can regulate mRNA transcription, protein translation and synthesis and precursor messenger RNA processing or alternative splicing. The effects of DDX5 on carcinogenesis and cancer progression are increasingly evident. Circular RNAs (circRNAs), a novel group of functionally non-coding RNAs (ncRNAs) with disordered expression, are associated with various pathological processes (e.g., tumors). circRNA pattern and its function regulated by DDX5 have not yet been determined. According to our findings, DDX5 was dramatically upregulated for stomach cancer tissues, and its overexpression contributed to the cell growth and invasion of GC cells. Based on the analysis of genome-wide circRNAs conducted with circRNA sequencing, DDX5 induces a large number of circRNAs. Further to screen several circRNAs from PHF14 for function, it was found that circPHF14 was essential for the growth and tumorigenesis of DDX5-positive gastric cancer cells. These findings suggest that in addition to the messenger RNA and microRNA patterns, DDX5 also effects a circRNA pattern, as demonstrated by circPHF14. DDX5-induced circRNAs have been found to be of crucial importance for the growth of DDX5-positive gastric cancer cells, providing a new therapeutic target.

The role of tripartite motif-containing 28 in cancer progression and its therapeutic potentials.

Tripartite motif-containing 28 (TRIM28) belongs to tripartite motif (TRIM) family. TRIM28 not only binds and degrades its downstream target, but also acts as a transcription co-factor to inhibit gene expression. More and more studies have shown that TRIM28 plays a vital role in tumor genesis and progression. Here, we reviewed the role of TRIM28 in tumor proliferation, migration, invasion and cell death. Moreover, we also summarized the important role of TRIM28 in tumor stemness sustainability and immune regulation. Because of the importance of TRIM28 in tumors, TIRM28 may be a candidate target for anti-tumor therapy and play an important role in tumor diagnosis and treatment in the future.

Analysis of genomic and immune intratumor heterogeneity in linitis plastica via multiregional exome and T-cell receptor sequencing.

The molecular landscape and the intratumor heterogeneity (ITH) architecture of gastric linitis plastica (LP) are poorly understood. We performed whole-exome sequencing (WES) and T-cell receptor (TCR) sequencing on 40 tumor regions from four LP patients. The landscape and ITH at the genomic and immunological levels in LP tumors were compared with multiple cancers that have previously been reported. The lymphocyte infiltration was further assessed by immunohistochemistry (IHC) in LP tumors. In total, we identified 6339 non-silent mutations from multi-samples, with a median tumor mutation burden (TMB) of 3.30 mutations per Mb, comparable to gastric adenocarcinoma from the Cancer Genome Atlas (TCGA) cohort (P = 0.53). An extremely high level of genomic ITH was observed, with only 12.42%, 5.37%, 5.35%, and 30.67% of mutations detectable across 10 regions within the same tumors of each patient, respectively. TCR sequencing revealed that TCR clonality was substantially lower in LP than in multi-cancers. IHC using antibodies against CD4, CD8, and PD-L1 demonstrated scant T-cell infiltration in the four LP tumors. Furthermore, profound TCR ITH was observed in all LP tumors, with no T-cell clones shared across tumor regions in any of the patients, while over 94% of T-cell clones were restricted to individual tumor regions. The Morisita overlap index (MOI) ranged from 0.21 to 0.66 among multi-regions within the same tumors, significantly lower than that of lung cancer (P = 0.002). Our results show that LP harbored extremely high genomic and TCR ITH and suppressed T-cell infiltration, suggesting a potential contribution to the frequent recurrence and poor therapeutic response of this adenocarcinoma.