Hypoxia-induced SENP3 promotes chemosensitivity and mitochondrial fission via deSUMOylation of Drp1.

OBJECTIVE: The study aimed to investigate the effect of the SUMOylation status of Drp1 on mitochondrial fission in CDDP-treated HNSCC cells cultured under hypoxic conditions. MATERIALS AND METHODS: The effect of hypoxia on the chemosensitivity of HNCC cells was evaluated by flow cytometry and CCK-8 assays. The biological function of SUMO-specific peptidase 3 (SENP3) was evaluated by loss-of-function assays both in vitro and in vivo. SENP3-regulated deSUMOylation of Drp1 were performed with co-IP assays. RESULTS: SENP3 expression correlated with chemosensitivity in clinical HNSCC samples subjected to hypoxic conditions. Hypoxia-induced ROS increased HIF-1α/SENP3 expression and mitochondrial fission in CDDP-treated HNSCC cells, and these effects were reversed by NAC treatment. SENP3 knockdown reversed hypoxia-induced mitochondrial fission and inhibited HNSCC cell apoptosis, which decreased CDDP sensitivity. Furthermore, hypoxia-induced SENP3 deconjugated SUMO2 from Drp1. CONCLUSION: Our findings revealed that hypoxia-induced SENP3 facilitates CDDP sensitivity and mitochondrial fission via deSUMOylation of Drp1.

Spatial Transcriptomic and Metabolomic Landscapes of Oral Submucous Fibrosis-Derived Oral Squamous Cell Carcinoma and its Tumor Microenvironment.

In South and Southeast Asia, the habit of chewing betel nuts is prevalent, which leads to oral submucous fibrosis (OSF). OSF is a well-established precancerous lesion, and a portion of OSF cases eventually progress to oral squamous cell carcinoma (OSCC). However, the specific molecular mechanisms underlying the malignant transformation of OSCC from OSF are poorly understood. In this study, the leading-edge techniques of Spatial Transcriptomics (ST) and Spatial Metabolomics (SM) are integrated to obtain spatial location information of cancer cells, fibroblasts, and immune cells, as well as the transcriptomic and metabolomic landscapes in OSF-derived OSCC tissues. This work reveals for the first time that some OSF-derived OSCC cells undergo partial epithelial-mesenchymal transition (pEMT) within the in situ carcinoma (ISC) region, eventually acquiring fibroblast-like phenotypes and participating in collagen deposition. Complex interactions among epithelial cells, fibroblasts, and immune cells in the tumor microenvironment are demonstrated. Most importantly, significant metabolic reprogramming in OSF-derived OSCC, including abnormal polyamine metabolism, potentially playing a pivotal role in promoting tumorigenesis and immune evasion is discovered. The ST and SM data in this study shed new light on deciphering the mechanisms of OSF-derived OSCC. The work also offers invaluable clues for the prevention and treatment of OSCC.

Role of adhesion molecules in cancer and targeted therapy.

Adhesion molecules mediate cell-to-cell and cell-to-extracellular matrix interactions and transmit mechanical and chemical signals among them. Various mechanisms deregulate adhesion molecules in cancer, enabling tumor cells to proliferate without restraint, invade through tissue boundaries, escape from immune surveillance, and survive in the tumor microenvironment. Recent studies have revealed that adhesion molecules also drive angiogenesis, reshape metabolism, and are involved in stem cell self-renewal. In this review, we summarize the functions and mechanisms of adhesion molecules in cancer and the tumor microenvironment, as well as the therapeutic strategies targeting adhesion molecules. These studies have implications for furthering our understanding of adhesion molecules in cancer and providing a paradigm for exploring novel therapeutic approaches.

Spatially Resolved Transcriptomics Technology Facilitates Cancer Research.

Single cell RNA sequencing (scRNA-seq) provides a great convenience for studying tumor occurrence and development for its ability to study gene expression at the individual cell level. However, patient-derived tumor tissues are composed of multiple types of cells including tumor cells and adjacent non-malignant cells such as stromal cells and immune cells. The spatial locations of various cells in situ tissues plays a pivotal role in the occurrence and development of tumors, which cannot be elucidated by scRNA-seq alone. Spatially resolved transcriptomics (SRT) technology emerges timely to explore the unrecognized relationship between the spatial background of a particular cell and its functions, and is increasingly used in cancer research. This review provides a systematic overview of the SRT technologies that are developed, in particular the more widely used cutting-edge SRT technologies based on next-generation sequencing (NGS). In addition, the main achievements by SRT technologies in precisely unveiling the underappreciated spatial locations on gene expression and cell function with unprecedented high-resolution in cancer research are emphasized, with the aim of developing more effective clinical therapeutics oriented to a deeper understanding of the interaction between tumor cells and surrounding non-malignant cells.

Application prospect of circular RNA-based neoantigen vaccine in tumor immunotherapy.

Neoantigen is a protein produced by mutant gene, which is only expressed in tumor cells. It is an ideal target for therapeutic tumor vaccines. Although synthetic long peptide (SLP)-based neoantigen vaccine, DNA-based neoantigen vaccine, and mRNA-based neoantigen vaccine are all in the development stage, they have some inherent shortcomings. Therefore, researchers turned their attention to a new type of "non-coding RNA (ncRNA)", circular RNA (circRNA), for potential better choice. Because of its unique high stability and protein-coding capacity, circRNA is a promising target in the field of neoantigen vaccine. In this paper, we reviewed the feasibility of circRNA encoding neoantigens, summarized the construction process, explained the mechanism of circRNA vaccine in vitro, and discussed the advantages and disadvantages of circRNA vaccine and possible combination with other immunotherapies.

Application of anatomy unit resection surgery for lateral basicranial surgical approach in oral squamous carcinoma.

BACKGROUND: The basicranial region lacks definite boundaries and includes various anatomical units. We developed a novel concept of the posterior oral anatomical complex (POAC) to identify these anatomical units in the basicranial region. OSCC with POAC involvement is termed posterior oral squamous cell carcinoma (POSCC) with poor prognosis. The principal aim of this study was to evaluate the effect of anatomy unit resection surgery (AUSR) on patients with POSCC. METHODS: A total of 120 POSCC patients who underwent radical surgical treatment were recruited for this study. These POSCC patients were treated with conventional surgery or AUSR. According to the extent of primary tumor resection in the AUSR group, the lateral basicranial surgical approach can be subdivided into four types: face-lateral approach I, face-lateral approach II, face-median approach or face-median and face-lateral combined approach. Facial nerve function was evaluated according to the House-Brackmann Facial Nerve Grading System. RESULTS: The overall survival rate was 62.5% and 37.5% in the AURS group and conventional group (hazard ratio: 0.59; p < 0.0001), respectively. The disease-free survival rate was 62.5% and 34.3% in the AURS group and conventional group (hazard ratio: 0.43; p = 0.0008), respectively. The local disease control rate in the AURS group (71.4%) was significantly better than that in the conventional group (34.4%) in present study (p < 0.0001). Compared to the conventional group, all the patients undergoing AURS were classified as T4 stage and presented with more lymph node metastasis (71.4%). A total of 20 patients (face-lateral approach I and face-lateral combined approach) were temporarily disconnected from the temporofacial branch of the facial nerve. Fifteen patients exhibited slight paresis, and five patients presented with moderate or severe paresis. The survival rate of zygomatic arch disconnection was 94.6% (54 of 56 patients). CONCLUSION: This lateral basicranial surgical approach based on AUSR improves the survival rate and enhances the local control rate while also preserving a good prognosis without damaging the nerve and zygomatic bone. This surgical approach based on AUSR provides a novel and effective surgical treatment to address POSCC with better prognosis, especially for patients without metastatic lymph nodes.

Circular RNA circPVT1 promotes nasopharyngeal carcinoma metastasis via the ß-TrCP/c-Myc/SRSF1 positive feedback loop.

BACKGROUND: Circular RNAs (circRNAs) act as gene expression regulators and are involved in cancer progression. However, their functions have not been sufficiently investigated in nasopharyngeal carcinoma (NPC). METHODS: The expression profiles of circRNAs in NPC cells within different metastatic potential were reanalyzed. Quantitative reverse transcription PCR and in situ hybridization were used to detect the expression level of circPVT1 in NPC cells and tissue samples. The association of expression level of circPVT1 with clinical properties of NPC patients was evaluated. Then, the effects of circPVT1 expression on NPC metastasis were investigated by in vitro and in vivo functional experiments. RNA immunoprecipitation, pull-down assay and western blotting were performed to confirm the interaction between circPVT1 and ß-TrCP in NPC cells. Co-immunoprecipitation and western blotting were performed to confirm the interaction between ß-TrCP and c-Myc in NPC cells. RESULTS: We find that circPVT1, a circular RNA, is significantly upregulated in NPC cells and tissue specimens. In vitro and in vivo experiments showed that circPVT1 promotes the invasion and metastasis of NPC cells. Mechanistically, circPVT1 inhibits proteasomal degradation of c-Myc by binding to ß-TrCP, an E3 ubiquiting ligase. Stablization of c-Myc by circPVT1 alters the cytoskeleton remodeling and cell adhesion in NPC, which ultimately promotes the invasion and metastasis of NPC cells. Furthermore, c-Myc transcriptionally upregulates the expression of SRSF1, an RNA splicing factor, and recruits SRSF1 to enhance the biosynthesis of circPVT1 through coupling transcription with splicing, which forms a positive feedback for circPVT1 production. CONCLUSIONS: Our results revealed the important role of circPVT1 in the progression of NPC through the ß-TrCP/c-Myc/SRSF1 positive feedback loop, and circPVT1 may serve as a prognostic biomarker or therapeutic target in patients with NPC.

Regulatory pathways and drugs associated with ferroptosis in tumors.

Ferroptosis is a type of cell death that depends on iron and reactive oxygen species (ROS). The accumulation of iron and lipid peroxidation primarily initiates oxidative membrane damage during ferroptosis. The core molecular mechanism of ferroptosis includes the regulation of oxidation and the balance between damage and antioxidant defense. Tumor cells usually contain a large amount of H2O2, and ferrous/iron ions will react with excessive H2O2 in cells to produce hydroxyl radicals and induce ferroptosis in tumor cells. Here, we reviewed the latest studies on the regulation of ferroptosis in tumor cells and introduced the tumor-related signaling pathways of ferroptosis. We paid particular attention to the role of noncoding RNA, nanomaterials, the role of drugs, and targeted treatment using ferroptosis drugs for mediating the ferroptosis process in tumor cells. Finally, we discussed the currently unresolved problems and future research directions for ferroptosis in tumor cells and the prospects of this emerging field. Therefore, we have attempted to provide a reference for further understanding of the pathogenesis of ferroptosis and proposed new targets for cancer treatment.

Extrachromosomal Circular DNA: A New Target in Cancer.

Genomic instability and amplification are intrinsically important traits determining the development and heterogeneity of tumors. The role of extrachromosomal circular DNA (eccDNA) in tumors has recently been highlighted. EccDNAs are unique genetic materials located off the chromosomal DNA. They have been detected in a variety of tumors. This review analyzes the mechanisms involved in the formation of eccDNAs and their genetic characteristics. In addition, the high-copy number and transcriptional levels of oncogenes located in eccDNA molecules contribute to the acceleration of tumor evolution and drug resistance and drive the development of genetic heterogeneity. Understanding the specific genomic forms of eccDNAs and characterizing their potential functions will provide new strategies for tumor therapy. Further research may yield new targets and molecular markers for the early diagnosis and treatment of human cancer.

Circular RNA circCCNB1 inhibits the migration and invasion of nasopharyngeal carcinoma through binding and stabilizing TJP1 mRNA.

Nasopharyngeal carcinoma (NPC) is a malignant tumor that usually occurs in people from Southeast Asia and Southern China. NPC is prone to migration and invasion, leading to poor prognosis. A large number of circular RNAs (circRNAs) exacerbate the process of metastasis in NPC; however, their underlying mechanisms remain unclear. We found that the circular RNA circCCNB1, encoded by the oncogene CCNB1, was downregulated in NPC biopsies and cell lines. In vitro assays show that circCCNB1 inhibits NPC cell migration and invasion. Moreover, circCCNB1 induces a protein, nuclear factor 90 (NF90), to bind and prolong the half-life of tight junction protein 1 (TJP1) mRNA. Upregulation of TJP1 enhances tight junctions between cancer cells and inhibits NPC cell migration and invasion. This study reveals a novel biological function of circCCNB1 in the migration and invasion of NPC by enhancing the tight junctions of cancer cells by binding to NF90 proteins and TJP1 mRNA, and may provide a potential therapeutic target for NPC.

Potential applications of N6 -methyladenosine modification in the prognosis and treatment of cancers via modulating apoptosis, autophagy, and ferroptosis.

N6 -methyladenosine (m6 A) is one of the most abundant modifications determining the fate of RNA. Currently, m6 A modification is tightly connected with tumorigenesis and presents novel promise in clinical applications. Regulated cell death (RCD) is a programmed mechanism that plays a complicated role in malignant transition. Regarding the main forms of RCD, aberrant levels of m6 A modification have been detected during the progression of apoptosis, autophagy, ferroptosis, necroptosis, and pyroptosis in several diseases. However, few reviews have elucidated the correlation between m6 A-modified RCD and carcinogenesis. In this review, we summarize the regulators of m6 A methylation and their functions in carcinogenesis through an overview of m6 A-modified RCD. Additionally, we assume the potential role of m6 A modification regulators as novel biomarkers for chemotherapies and precision medicine. Furthermore, we review the controversies and conflicts in m6 A explorations and predict future orientations of m6 A-modified RCD for clinical applications. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs.

EBV miRNAs BART11 and BART17-3p promote immune escape through the enhancer-mediated transcription of PD-L1.

Epstein-Barr virus (EBV) is reportedly the first identified human tumor virus, and is closely related to the occurrence and development of nasopharyngeal carcinoma (NPC), gastric carcinoma (GC), and several lymphomas. PD-L1 expression is elevated in EBV-positive NPC and GC tissues; however, the specific mechanisms underlying the EBV-dependent promotion of PD-L1 expression to induce immune escape warrant clarification. EBV encodes 44 mature miRNAs. In this study, we find that EBV-miR-BART11 and EBV-miR-BART17-3p upregulate the expression of PD-L1 in EBV-associated NPC and GC. Furthermore, EBV-miR-BART11 targets FOXP1, EBV-miR-BART17-3p targets PBRM1, and FOXP1 and PBRM1 bind to the enhancer region of PD-L1 to inhibit its expression. Therefore, EBV-miR-BART11 and EBV-miR-BART17-3p inhibit FOXP1 and PBRM1, respectively, and enhance the transcription of PD-L1 (CD274, http://www.ncbi.nlm.nih.gov/gene/29126 ), resulting in the promotion of tumor immune escape, which provides insights into potential targets for EBV-related tumor immunotherapy.

Evaluating the Role of Low Molecular Heparin to Prevent Anterolateral Thigh Flap Compromise in 2460 Head and Neck Defect Cases.

PURPOSE: Since thrombosis is the leading cause of free flap failure, anticoagulant agents appear to improve free flap survival by decreasing the probability of thrombus formation. This retrospective study primarily aimed to evaluate the outcomes and complications of anterolateral thigh flap (ALT) transfer in patients who were postoperatively treated with or without low molecular weight heparin (LMWH) calcium. METHODS: This was a retrospective study. The sample comprised patients who underwent ALT transfer between January 2015 and January 2020 in the Department of Oral and Maxillofacial Surgery at the Second Xiangya Hospital. The predictor variable was LMWH. The outcome variable was flap compromise. Other study variables were age, sex, defect location, hypertension, diabetes, number of vein anastomoses, alcohol history, radiation history, and hematoma. Descriptive, bivariate, and regression statistics were computed, and the P value was set at 0.05. RESULTS: The sample was composed of 2460 patients, comprising 2,234 males and 226 females, with a mean age of 50.5 years (range, 19-79 years). Based on the use of LMWH, the patients were divided into experimental and control groups. There were no significant differences in the clinical characteristics between the groups. Moreover, there were no significant differences in flap compromise or hematoma incidence between the groups. In the logistic regression model for flap compromise, the only factor found to be associated with flap compromise was hematoma (P < .0001). CONCLUSION: The use of LMWH in head and neck free flap transfer does not reduce the incidence of thrombosis and flap compromise.

The influence of circular RNAs on autophagy and disease progression.

Circular RNAs (circRNAs) are non-coding RNAs that have attracted considerable attention in recent years. Owing to their distinct circular structure, circRNAs are stable in cells. Autophagy is a catabolic process that helps in the degradation and recycling of harmful or inessential biological macromolecules in cells and enables cells to adapt to stress and changes in the internal and external environments. Evidence has shown that circRNAs influence the course of a disease by regulating autophagy, which indicates that autophagy is involved in the onset and development of various diseases and can affect drug resistance (for example, it affects cisplatin resistance in tumors). In this review, we summarized the role of circRNAs in autophagy and their influence on disease onset and progression as well as drug resistance. The review will expand our understanding of tumors as well as cardiovascular and neurological diseases and also suggest novel therapeutic strategies.Abbreviations: ACR: autophagy-related circRNA; ADSCs: adipogenic mesenchymal stem cells; AMPK: AMP-activated protein kinase; ATG: autophagy related; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; ceRNA: competing endogenous RNA; circRNA: circular RNA; CMA: chaperone-mediated autophagy; EPCs: endothelial progenitor cells; LE/MVBs: late endosomes/multivesicular bodies; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NSCLC: non-small cell lung cancer; PDLSCs: periodontal ligament stem cells; PE: phosphatidylethanolamine; PtdIns: phosphatidylinositol; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate 1,2-dipalmitoyl; PTEN: phosphatase and tensin homolog; RBPs: RNA-binding proteins; SiO2: silicon dioxide; TFEB: transcription factor EB; ULK: unc-51 like autophagy activating kinase 1.

BPIFB1 inhibits vasculogenic mimicry via downregulation of GLUT1-mediated H3K27 acetylation in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) demonstrates significant regional differences and a high incidence in Southeast Asia and Southern China. Bactericidal/permeability-increasing-fold- containing family B member 1 (BPIFB1) is a relatively specific and highly expressed protein in the nasopharyngeal epithelium. BPIFB1 expression is substantially downregulated in NPC and is significantly associated with poor prognosis in patients with NPC. However, the specific molecular mechanism by which BPIFB1 regulates NPC is not well understood. In this study, we found that BPIFB1 inhibits vasculogenic mimicry by regulating the metabolic reprogramming of NPC. BPIFB1 decreases GLUT1 transcription by downregulating the JNK/AP1 signaling pathway. Altered glycolysis reduces the acetylation level of histone and decreases the expression of vasculogenic mimicry-related genes, VEGFA, VE-cadherin, and MMP2, ultimately leading to the inhibition of vasculogenic mimicry. To our knowledge, this is the first report on the role and specific mechanism of BPIFB1 as a tumor suppressor gene involved in regulating glycolysis and vasculogenic mimicry in NPC. Overall, these results provide a new therapeutic target for NPC diagnosis and treatment.

Long non-coding RNAs are involved in alternative splicing and promote cancer progression.

Alternative splicing (AS) is a key process in which precursor RNAs produce different mature RNAs, and the disorder of AS is a key factor in promoting cancer development. Compared with coding RNA, studies on the functions of long non-coding RNAs (lncRNAs) are far from enough. In fact, lncRNA is an important participant and regulator in the process of AS. On the one hand, lncRNAs regulate cancer progression as AS products of precursor messenger RNA (mRNA), but on the other hand, precursor lncRNA generates cancer-related abnormal splicing variants through AS. In addition, lncRNAs directly or indirectly regulate the AS events of downstream target genes, thus affecting the occurrence and development of cancer. Here, we reviewed how lncRNAs regulate AS and influence oncogenesis in different ways.

A fluorescence strategy for circRNA quantification in tumor cells based on T7 nuclease-assisted cycling enzymatic amplification.

Circular Ribonucleic Acid (CircRNA) plays regulatory roles in many biological processes, such as tumors and metabolic diseases. Due to the fact that circRNA is more stable and conservative than linear RNA, circRNA has become a potential biomarker in early clinical diagnosis and biomedical research. Therefore, the quantification of circRNA expression level is of importance for understanding their functions and their applications for disease diagnosis and treatment. Nevertheless, due to the low abundance of circRNA, it is still a challenge for the analysis of circRNA in cells. Herein, we proposed a sensitive detection method for circRNA based on the T7 exonuclease-assisted cycling enzymatic amplification. The fluorescent sensor was constructed by a hairpin molecular beacon and T7 exonuclease. With the cycling enzymatic amplification process, this sensor achieved the limit of detection of 1 pM with a good linear correlation in the range of 0-100 pM (R2 = 0.9891) using circBART2.2 as a model. Furthermore, we applied the proposed method in the determination of circBART2.2 in cell lysates. The results demonstrated that this method has promising applications in early diagnosis of Epstein-Barr virus (EBV) infection-related diseases using circRNA as the biomarker.

Recent advances of fluorescent biosensors based on cyclic signal amplification technology in biomedical detection.

The cyclic signal amplification technology has been widely applied for the ultrasensitive detection of many important biomolecules, such as nucleic acids, proteins, enzymes, adenosine triphosphate (ATP), metal ions, exosome, etc. Due to their low content in the complex biological samples, traditional detection methods are insufficient to satisfy the requirements for monitoring those biomolecules. Therefore, effective and sensitive biosensors based on cyclic signal amplification technology are of great significance for the quick and simple diagnosis and treatment of diseases. Fluorescent biosensor based on cyclic signal amplification technology has become a research hotspot due to its simple operation, low cost, short time, high sensitivity and high specificity. This paper introduces several cyclic amplification methods, such as rolling circle amplification (RCA), strand displacement reactions (SDR) and enzyme-assisted amplification (EAA), and summarizes the research progress of using this technology in the detection of different biomolecules in recent years, in order to provide help for the research of more efficient and sensitive detection methods.

The role of alternative splicing in human cancer progression.

In eukaryotes, alternative splicing refers to a process via which a single precursor RNA (pre-RNA) is transcribed into different mature RNAs. Thus, alternative splicing enables the translation of a limited number of coding genes into a large number of proteins with different functions. Although, alternative splicing is common in normal cells, it also plays an important role in cancer development. Alteration in splicing mechanisms and even the participation of non-coding RNAs may cause changes in the splicing patterns of cancer-related genes. This article reviews the latest research on alternative splicing in cancer, with a view to presenting new strategies and guiding future studies related to pathological mechanisms associated with cancer.

Reconstruction of Complex Lateral Skull Base Defects After Oral Cancer Resection With Individualized Anterolateral Thigh Flap.

OBJECTIVES: Complex lateral skull base defects resulting from advanced or recurrent oral cancer resection are continuously challenging reconstructive surgeons. This study aimed to use reconstructive methods for lateral skull base defects, explore their feasibility, and evaluate the efficacy of defect reconstruction using anterolateral thigh (ALT) flaps. PATIENTS AND METHODS: We performed a retrospective case series of 37 patients who underwent lateral skull base defect reconstruction using the ALT/anteromedial thigh (AMT) flap between March 2016 and May 2021 at the Second Xiangya Hospital. The design and harvest of the flaps, methods for defect reconstruction, and reconstructive efficacy are described. RESULTS: Of the 37 patients, 3 were women and 34 were men, with a mean age of 51.7 years. Among the defects, 26 were through-and-through defects and were reconstructed using ALT chimeric flaps, double ALT flaps, folded ALT flap, combined ALT chimeric flaps and AMT flaps, or combined ALT chimeric flaps and pectoralis major flaps; the large lateral skull base dead spaces were filled with muscle tissues or fatty tissues. Postoperatively, 38 of the 39 ALT/AMT flaps survived completely, and the remaining flap experienced partial necrosis. Venous compromise occurred in one patient who was salvaged after operative exploration. Oral and maxillofacial wound infections occurred in two patients, salivary fistula in three patients, and thigh wound effusion in three patients. The wounds healed gradually in all patients after repeated dressing changes. Thirty-three patients were followed up for approximately 3-60 months; their oral functions and appearance were acceptable, and thigh motor dysfunction was not observed. CONCLUSIONS: With the convenient flap design and muscle flap harvest, large and individualized tissue supply, feasible combination with other flaps, effective reduction or avoidance of wound complications, and acceptable donor site morbidity, the ALT flap is an appropriate choice for complex lateral skull base defect reconstruction.