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.

Splicing inhibition mediated by reduced splicing factors and helicases is associated with the cellular response of lung cancer cells to cisplatin.

Lung cancer's mortality is predominantly linked to post-chemotherapy recurrence, driven by the reactivation of dormant cancer cells. Despite the critical role of these reactivated cells in cancer recurrence and metastasis, the molecular mechanisms governing their therapeutic selection remain poorly understood. In this study, we conducted an integrative analysis by combining PacBio single molecule real-time (SMRT) sequencing with short reads Illumina RNA-seq. Our study revealed that cisplatin-induced dormant and reactivated cancer cells exhibited a noteworthy reduction in gene transcripts and alternative splicing events. Particularly, the differential alternative splicing events were found to be overlapping with the differentially expression genes and enriched in genes related to cell cycle and cell division. Utilizing ENCORI database and correlation analysis, we identified key splicing factors, including SRSF7, SRSF3, PRPF8, and HNRNPC, as well as RNA helicase such as EIF4A3, DDX39A, DDX11, and BRIP1, which were associated with the observed reduction in alternative splicing and subsequent decrease in gene expression. Our study demonstrated that lung cancer cells reduce gene transcripts through diminished alternative splicing events mediated by specific splicing factors and RNA helicase in response to the chemotherapeutic stress. These findings provide insights into the molecular mechanisms underlying the therapeutic selection and reactivation of dormant cancer cells. This discovery opens a potential avenue for the development of therapeutic strategies aimed at preventing cancer recurrence following chemotherapy.

LRP6 is a potential biomarker of kidney clear cell carcinoma related to prognosis and immune infiltration.

Renal cell carcinoma is the most common and most lethal genitourinary tumor. The causes of renal clear cell carcinoma are complex and the heterogeneity of the tumor tissue is high, so patient outcomes are not very satisfactory. Exploring biomarkers in the progression of renal clear cell carcinoma is crucial to improve the diagnosis and guide the treatment of renal clear cell carcinoma. LRP6 is a co-receptor of the Wnt/ß-catenin signaling pathway, which is involved in cell growth, inflammation and cell transformation through activation of the Wnt/ß-catenin signaling pathway. Abnormal expression of LRP6 is associated with the malignant phenotype, metastatic potential and poor prognosis of various tumors. In this study, we found that LRP6 was abnormally highly expressed in a variety of tumors and significantly correlated with microsatellite instability, tumor mutation burden, and immune cell infiltration and immune checkpoint expression in a variety of tumors. Moreover, we found that LRP6 was significantly associated with the prognosis of renal clear cell carcinoma. Further we found a significant correlation between LRP6 and the expression of m6A-related genes and ferroptosis-related genes. Finally, we also found a significant correlation between the expression of LRP6 and the sensitivity to common drugs used in kidney clear cell carcinoma treatment. These results suggest that LRP6 is likely to be a potential target for kidney clear cell carcinoma treatment.

EphB1 promotes the differentiation and maturation of dendritic cells in non-small cell lung cancer.

EphB1 is implicated in numerous physiological and pathological processes, including nervous system diseases, cardiovascular diseases and cancers. It binds to membrane-bound ligands and drives bidirectional signaling. EphB1, along with its ligand ehrinB, plays a pivotal role in activating immune cells. However, despite its presence in dendritic cells (DCs), EphB1's involvement in the differentiation and maturation of DCs in cancers remains inadequately understood. In this study, we found compromised differentiation and maturation of DCs in EphB1-/- mice bearing lung adenocarcinoma syngeneic tumors. Our in vitro assays revealed that EphB1 phosphorylation induced DC differentiation and maturation. Cox-2, a key enzyme involved in the production of proinflammatory molecules, is implicated in DC differentiation induced by phosphorylated EphB1. Additionally, the study has identified lead compounds that specifically target EphB1 phosphorylation sites. Collectively, this research on EphB1 phosphorylation has provided valuable insights into the regulation of immune cell functionality and holds the potential for the development of innovative therapeutic strategies for a range of diseases.

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.

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.

The Eph/Ephrin system in primary bone tumor and bone cancer pain.

The family of Eph receptor tyrosine kinases and their Ephrin ligands system constitutes a bidirectional signaling pathway. Eph/Ephrin system coordinate a wide spectrum of pathologic processes during development, metastasis, prognosis, drug resistance and angiogenesis in carcinogenesis. Chemotherapy, surgery and radiotherapy are the most commonly used clinical treatments for primary bone tumors. Therefore, surgical resection is often unable to completely eliminate the tumor, and this is the main cause of metastasis and postoperative recurrence. A growing body of literature has been published lately revitalizing our scientific interest towards the role of Eph/Ephrins in pathogenesis and the treatment of bone tumor and bone cancer pain. This study mainly reviewed the roles of Eph/Ephrin system that has both tumor-suppressing and -promoting roles in primary bone tumors and bone cancer pain. Understanding the intracellular mechanisms of Eph/Ephrin system in tumorigenesis and metastasis of bone tumors might provide a foundation for the development of Eph/Ephrin targeted anti-cancer therapy.

Antimicrobial Peptides: A Promising Strategy for Anti-tuberculosis Therapeutics.

The high global burden of tuberculosis (TB) and the increasing emergence of the drugresistant (DR) strain of Mycobacterium tuberculosis (Mtb) emphasize the urgent need for novel antimycobacterial agents. Antimicrobial peptides (AMPs) are small peptides widely existing in a variety of organisms and usually have amphiphilic cationic structures, which have a selective affinity to the negatively charged bacterial cell wall. Besides direct bactericidal mechanisms, including interacting with the bacterial cell membrane and interfering with the biosynthesis of the cell wall, DNA, or protein, some AMPs are involved in the host's innate immunity. AMPs are promising alternative or complementary agents for the treatment of DR-TB, given their various antibacterial mechanisms and low cytotoxicity. A large number of AMPs, synthetic or natural, from human to bacteriophage sources, have displayed potent anti-mycobacterial activity in vitro and in vivo. In this review, we summarized the features, antimycobacterial activity, and mechanisms of action of the AMPs according to their sources. Although AMPs have not yet met the expectations for clinical application due to their low bioavailabilities, high cost, and difficulties in large-scale production, their potent antimycobacterial activity and action mechanisms, which are different from conventional antibiotics, make them promising antibacterial agents against DR-Mtb in the future.

Exosomal ITGB6 from dormant lung adenocarcinoma cells activates cancer-associated fibroblasts by KLF10 positive feedback loop and the TGF-ß pathway.

Background: Dormant cancer cells are commonly known to play a pivotal role in cancer recurrence and metastasis. However, the mechanism of tumor dormancy and recurrence remains largely unknown. This study aimed to investigate the mechanism by which exosomes derived from dormant lung adenocarcinoma (LUAD) cells activate cancer-associated fibroblasts (CAFs) to reconstruct the extracellular matrix (ECM), providing a novel idea for decoding the mechanism of tumor dormancy. Methods: In this study, high-dose cisplatin was used to induce the dormant LUAD cells. Exosomes were extracted from the culture supernatant of normal and dormant cancer cells. The effects of selected exosomal proteins on the fibroblasts were evaluated. RNA-seq for fibroblasts and exosomal proteomics for normal and dormant cancer cells were used to identify and verify the mechanism of activating fibroblasts. Results: We demonstrated that exosomes derived from dormant A549 cells could be taken by fibroblasts. Exosomal ITGB6 transferred into fibroblasts induced the activation of CAFs by activating the KLF10 positive feedback loop and transforming growth factor ß (TGF-ß) pathway. High ITGB6 expression was associated with activation of the TGF-ß pathway and ECM remodeling. Conclusions: In all, we demonstrated that CAFs were activated by exosomes from dormant lung cancer cells and reconstruct ECM. ITGB6 may be a critical molecule for activating the TGF-ß pathway and remodeling ECM.

Exosomes from cisplatin-induced dormant cancer cells facilitate the formation of premetastatic niche in bone marrow through activating glycolysis of BMSCs.

Introduction: Lung cancer is the leading cause of cancer-related deaths worldwide. Chemotherapy kills most cancer cells; however, residual cells enter a dormant state. The dormant cancer cells can be reactivated under specific circumstances. The "premetastatic niche" that is suitable for colonization of cancer cells is formed before the arrival of cancer cells. Tumor-derived exosomes are the main mediators of tumorigenesis. We are aiming to elucidate the roles of exosomes from cisplatin-induced dormant lung cancer cells in the formation of premetastatic niches in bone marrow. Methods: We performed differential proteomics in dormant A549 cell- and A549 cell-derived exosomes. Non-targeted metabolomics and RNA sequencing were performed to explore the molecular and metabolic reprogramming of bone marrow stromal cells (BMSCs). The growth and metastasis of A549 cells in vivo were monitored by bioluminescence imaging. Results: We found that Insulin-like growth factor 2 (IGF-2) and Insulin-like growth factor binding protein 2 (IGFBP2) were upregulated in dormant A549 cell-derived exosomes. BMSCs that took up exosomes from dormant A549 cells showed enhanced glycolysis and promoted the growth and metastasis of A549 cells possibly through Insulin-like growth factor 1 receptor (IGF-1R)-induced metabolic reprogramming. Inhibition of the production of lactate and IGF-1R signaling can suppress the growth and metastasis of A549 cells from bone marrow. Discussion: Overall, we demonstrated that BMSCs formed a premetastatic niche upon taking up exosomes from cisplatin-induced dormant lung cancer cells. BMSCs promoted lung cancer cell growth and metastasis through the reverse Warburg effect.

Cell-cell contact-driven EphB1 cis- and trans- signalings regulate cancer stem cells enrichment after chemotherapy.

Reactivation of chemotherapy-induced dormant cancer cells is the main cause of relapse and metastasis. The molecular mechanisms underlying remain to be elucidated. In this study, we introduced a cellular model that mimics the process of cisplatin responsiveness in NSCLC patients. We found that during the process of dormancy and reactivation induced by cisplatin, NSCLC cells underwent sequential EMT-MET with enrichment of cancer stem cells. The ATAC-seq combined with motif analysis revealed that OCT4-SOX2-TCF-NANOG motifs were associated with the enrichment of cancer stem cells induced by chemotherapy. Gene expression profiling suggested a dynamic regulatory mechanism during the process of enrichment of cancer stem cells, where Nanog showed upregulation in the dormant state and SOX2 showed upregulation in the reactivated state. Further, we showed that EphB1 and p-EphB1 showed dynamic expression in the process of cancer cell dormancy and reactivation, where the expression profiles of EphB1 and p-EphB1 showed negatively correlated. In the dormant EMT cells which showed disrupted cell-cell contacts, ligand-independent EphB1 promoted entry of lung cancer cells into dormancy through activating p-p38 and downregulating E-cadherin. On the contrary, in the state of MET, in which cell-cell adhesion was recovered, interactions of EphB1 and ligand EphrinB2 in trans promoted the stemness of cancer cells through upregulating Nanog and Sox2. In conclusion, lung cancer stem cells were enriched during the process of cellular response to chemotherapy. EphB1 cis- and trans- signalings function in the dormant and reactivated state of lung cancer cells respectively. It may provide a therapeutic strategy that target the evolution process of cancer cells induced by chemotherapy.

Amentoflavone impairs the reconsolidated fear memories through inhibition of ERK pathway.

Post-traumatic stress disorder (PTSD) is a pathological fear memory-related disease. The persistence of pathological fearful memories is one of the most characteristic symptoms of PTSD. However, this can be eliminated by intervening in reconsolidation. Inflammation is intimately involved in the pathophysiologic progression of PTSD. Amentoflavone (AF) has anti-inflammatory effects. However, the effect of AF on fear memory reconsolidation remains unclear. In the present series of experiments, the CFC paradigm of rats were constructed. This was followed by AF administration immediately after exposure to the conditioning chamber to observe the maintenance of fear memory. Finally, a Western blot for the amygdala was used to explore the possible molecular biological mechanisms of AF affecting animal behavior. The findings suggest that re-exposure to the conditioning chamber for retrieval of CFC memory followed by immediate intragastric AF administration in rats attenuated the fear response for at least 14 days. In addition, the Western blot results show that the CFC memory intervention effect of AF administration during the reconsolidation phase may be related to the ERK signaling pathway inhibition. In general, the administration of AF in the reconsolidation phase to inhibit neuroinflammation can block the reconsolidation process and disrupt fear memory retention in the long term, at least in part through ERK pathway.

Chromatin accessibility regulates chemotherapy-induced dormancy and reactivation.

Cisplatin-based chemotherapy remains the standard care for non-small cell lung cancer (NSCLC) patients. Relapse after chemotherapy-induced dormancy affects the overall survival of patients. The evolution of cancer cells under chemotherapy stress is regulated by transcription factors (TFs) with binding sites initially buried deep within inaccessible chromatin. The transcription machinery and dynamic epigenetic alterations during the process of dormancy-reactivation of lung cancer cells after chemotherapy need to be investigated. Here, we investigated the chromatin accessibility of lung cancer cells after cisplatin treatment, using an assay for transposase-accessible chromatin sequencing (ATAC-seq). We observed that global chromatin accessibility was extensively improved. Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining (TRRUST) v.2 was used to elucidate TF-target interaction during the process of dormancy and reactivation. Enhancer regions and motifs specific to key TFs including JUN, MYC, SMAD3, E2F1, SP1, CTCF, SMAD4, STAT3, NFKB1, and KLF4 were enriched in differential loci ATAC-seq peaks of dormant and reactivated cancer cells induced by chemotherapy. The findings suggest that these key TFs regulated gene expressions during the process of dormancy and reactivation of cancer cells through altering promoter accessibility of target genes. Our study helps advance understanding of how cancer cells adapt to the stress induced by chemotherapy through TF binding motif accessibility.

Proteomic profiling of extracellular vesicles and particles reveals the cellular response to cisplatin in NSCLC.

BACKGROUND: Cisplatin-based chemotherapy is a therapeutic strategy against non-small cell lung cancer (NSCLC). However, cancers relapse after chemotherapy due to a dormant state of residual cancer cells. Extracellular vesicles and particles (EVPs) are active carriers of proteins and nucleic acid. Here, we aimed to study the molecular alterations and proteomic characteristics of EPV in dormant and reactivated cancer cells induced by cisplatin. METHODS: We used a short-term single dose of cisplatin to induce the dormant and reactivated cell status. We examined the gene expressional profiling and proteomic profiling of EVPs from dormant and reactivated cancer cells by RNA-sequencing and LC-MS/MS. RESULTS: We found substantial changes in gene expression and protein level in EVP. The genes with higher expression in dormant cancer cells were lipid transporter- and lipid metabolic-related genes. A total of 111 EVP proteins were upregulated in dormant cancer cells compared to those in control cells. Fifty differential expressed proteins (DEPs) were identified in EVPs from reactivated cancer cells compared to those in dormant cancer cells. Among the DEPs, we found that apolipoproteins such as APOA1 and APOE were significantly increased in dormant cancer cell-derived EVPs. Integration of EVP proteomes with transcriptional profiles of cancer cells revealed that the proteomic profiling of EVP derived from cancer cells can reflect the cellular status of cancer cells, which showed an activated lipid metabolism in dormant state. CONCLUSION: Lipoproteins enriched in EVPs reflect the activated lipid metabolism in dormant cancer cells and may provide potential biomarkers or therapeutic targets for cisplatin-based therapy.

Lung microbiome alterations in NSCLC patients.

Lung is colonized by a diverse array of microbes and the lung microbiota is profoundly involved in the development of respiratory diseases. There is little knowledge about the role of lung microbiota dysbiosis in lung cancer. In this study, we performed metagenomic sequencing on bronchoalveolar lavage (BAL) from two different sampling methods in non-small cell lung cancer (NSCLC) patients and non-cancer controls. We found the obvious variation between bronchoscopy samples and lobectomy samples. Oral taxa can be found in both bronchoscopy and lobectomy samples and higher abundance of oral taxa can be found in bronchoscopy samples. Although the NSCLC patients had similar microbial communities with non-cancer controls, rare species such as Lactobacillus rossiae, Bacteroides pyogenes, Paenibacillus odorifer, Pseudomonas entomophila, Magnetospirillum gryphiswaldense, fungus Chaetomium globosum et al. showed obvious difference between NSCLC patients and non-cancer controls. Age-, gender-, and smoking-specific species and EGFR expression-related species in NSCLC patients were detected. There results implicated that different lung segments have differential lung microbiome composition. The oral taxa are found in the lobectomy samples suggesting that oral microbiota are the true members of lung microbiota, rather than contamination during bronchoscopy. Lung cancer does not obviously alter the global microbial composition, while rare species are altered more than common species. Certain microbes may be associated with lung cancer progression.

Microbiome Related Cytotoxically Active CD8+ TIL Are Inversely Associated With Lung Cancer Development.

Lung cancer is the most common cancer type around the world. Although major advances in cancer therapy, lung cancer has been the largest proportion of all cancer-related deaths. The respiratory tract contains many types of bacteria and a distinct lung microbiome in lung cancer patients was described in many studies. The specific roles of these lung microorganisms in lung cancer progression remain unclear. In this study, we evaluated the effect of inhalation of bronchoalveolar fluid (BAL) in the lung cancer cell growth. The microbiome-based immune and carcinogenesis was examined in tumor-bearing mouse model. We found that inhalation of BAL collected from non-small cell lung cancer (NSCLC) patients altered the lung microbiota and inhibited tumor cell growth. The inhibitory effect was due to the infiltration of CD3 and CD8+ T cells and decrease of M2 macrophages in lungs. The microbial communities of NSCLC BAL inhalation group were dominated by Pasteurella, whereas the microbial communities of non-cancer control and PBS inhalation group were dominated by Delftia. Linear discriminant analysis (LDA) indicated that the genera Pasteurella, Pseudomonas, and Chryseobacterium were increased in NSCLC BAL inhalation group, while genera Delftia, Ezakiella, Blautia, Cloacibacterium, and Microvirga et al. were increased in PBS and Non-cancer group. We demonstrated a significant positive correlation between Pasteurella and cytotoxic CD8+ TIL and a negative correlation with M2 macrophages. Coriobacteriaceae was positively correlated with M2 macrophages and negatively correlated with CD8+ cells. The abundance of Pasteurella was negatively correlated with tumor cell growth. Our findings provide a promising strategy that can be used as a therapeutic vaccine for lung cancer patients.

Serine/arginine-rich splicing factors: the bridge linking alternative splicing and cancer.

The serine/arginine-rich splicing factors (SRs) belong to the serine arginine-rich protein family, which plays an extremely important role in the splicing process of precursor RNA. The SRs recognize the splicing elements on precursor RNA, then recruit and assemble spliceosome to promote or inhibit the occurrence of splicing events. In tumors, aberrant expression of SRs causes abnormal splicing of RNA, contributing to proliferation, migration and apoptosis resistance of tumor cells. Here, we reviewed the vital role of SRs in various tumors and discussed the promise of analyzing mRNA alternative splicing events in tumor. Further, we highlight the challenges and discussed the perspectives for the identification of new potential targets for cancer therapy via SRs family members.