Cullin-RING Ligase 4 in Cancer: Structure, Functions, and Mechanisms.

Cullin-RING ligase 4 (CRL4) has attracted enormous attentions because of its extensive regulatory roles in a wide variety of biological and pathological events, especially cancer-associated events. CRL4 exerts pleiotropic effects by targeting various substrates for proteasomal degradation or changes in activity through different internal compositions to regulate diverse events in cancer progression. In this review, we summarize the structure of CRL4 with manifold compositional modes and clarify the emerging functions and molecular mechanisms of CRL4 in a series of cancer-associated events.

JARID2, a novel regulatory factor, promotes cell proliferation, migration, and invasion in oral squamous cell carcinoma.

BACKGROUND: Accurate regulation of gene expression is crucial for normal development and function of cells. The prognostic significance and potential carcinogenic mechanisms of the related gene JARID2 in OSCC are not yet clear, but existing research has indicated a significant association between the two. METHODS AND MATERIALS: The relationship between the expression of the JARID2 gene in tumor samples of OSCC patients and clinical pathological factors was analyzed using immunohistochemistry experiments and RT-qPCR analysis. Based on the clinical pathological data of patients, bioinformatics analysis was conducted using public databases to determine the function of JARID2 in OSCC. Knockdown OSCC cell lines were constructed, and the impact of JARID2 on the biological behavior of OSCC cell lines was assessed through CCK-8, wound healing assay, and transwell analysis. RESULTS: Immunohistochemistry experiments confirmed the correlation between JARID2 and the prognosis of OSCC patients, while RT-qPCR experiments demonstrated its expression levels in tissue and cells. CKK-8 experiments, wound healing assays, and Transwell experiments indicated that knocking down JARID2 had a negative impact on the proliferation, invasion, and migration of OSCC cells. Bioinformatics analysis results showed that the expression of JARID2 in OSCC is closely associated with patient gene co-expression, gene function enrichment, immune infiltration, and drug sensitivity. CONCLUSION: Our study indicates that JARID2 is a novel prognostic biomarker and potential therapeutic target for OSCC.

Areca nut-induced AREG promote oral epithelial cell proliferation, migration, and EMT.

OBJECTIVE: To analyze the biological effect and mechanism of areca nut extract (ANE) on human oral keratinocyte (HOK) cells. MATERIALS AND METHODS: The effect of gradient concentration of ANE on the proliferation activity of HOK cells was analyzed by cell counting kit-8 (CCK-8) assays. The differentially expressed genes between the ANE group and control group HOK cells were analyzed by second-generation transcriptome sequencing. Real-time PCR and western blot were, respectively, used to analyze the expression of AREG gene and protein in HOK cells. After AREG gene overexpression or knockdown, the proliferation, migration, and expression of proteins related to epithelial-mesenchymal transformation (EMT), MAPK signal pathway in HOK cells were, respectively, detected by CCK-8, wound healing, transwell, and western blot assays. RESULTS: ANE (500 µg/mL) promoted the proliferation and migration of HOK cells, ANE (2 mg/mL) promoted the EMT of HOK cells, and ANE (50 mg/mL) inhibited the proliferation of HOK cells. AREG knockdown inhibited ANE-induced proliferation and migration of HOK cells, while AREG overexpression promoted the proliferation and migration of HOK cells. Western blot assay showed that ANE activated MAPK signal pathway by upregulating AREG protein in HOK cells. CONCLUSIONS: ANE promoted HOK cell proliferation, migration, and EMT by mediating AREG-MAPK signaling pathway.

BCAT1 promotes cell proliferation, migration, and invasion via the PI3K-Akt signaling pathway in oral squamous cell carcinoma.

OBJECTIVES: To analyze the expression, biological function of branched chain amino-acid transaminase 1 (BCAT1) in oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Real-time PCR and immunohistochemistry were used to analyze the expression of BCAT1 protein in OSCC and normal oral tissues. Based on the clinicopathological information of patients, the relationship between the expression of BCAT1 protein and other clinicopathological factors was analyzed. Real-time PCR and western blot assays were used to analyze the expression of BCAT1 gene and protein in normal human oral keratinocytes (HOK) and human OSCC cells, respectively. After BCAT1 overexpression or knockdown, the proliferation, cell cycle, migration, and invasion of human OSCC cells were analyzed by CCK8, flow cytometry, wound healing, and transwell invasion assays, respectively. After adding the BCAT1 inhibitor EGR240 to OSCC cells, the changes in cell proliferation, migration, and invasion ability in OSCC cells were analyzed. Based on the TCGA database, the involved signal pathway in BCAT1-related and BCAT1-binding genes was obtained for Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, verified by western blot assays. After inhibiting PI3K, the effect of BCAT1 on the expression of the downstream phosphorylated protein of the PI3K-Akt signaling pathway was analyzed by western blot assays. The relationship between the expression of BCAT1 and EMT-related protein of OSCC cells was also analyzed. RESULTS: The expression of BCAT1 gene and protein were upregulated in OSCC tissue, which positively correlated with the pathological grade of patients with OSCC. Compared with normal oral keratinocytes, BCAT1 gene and protein were upregulated in OSCC cells. BCAT1 overexpression promoted the proliferation, migration, and invasion of OSCC cells. BCAT1 knockdown or inhibition could reduce the proliferation, migration, and invasion abilities of OSCC cells. The results of bioinformatics analysis and Western bolt showed that BCAT1 could regulate the activation of PI3K-Akt signaling pathway, and promote epithelial-mesenchymal transition (EMT) of OSCC cells. CONCLUSIONS: BCAT1 could promote the proliferation, migration, and invasion of OSCC cells via PI3K-Akt signaling pathway, which is a potential therapeutic target for OSCC.

circMTO1/miR-30c-5p/SOCS3 axis alleviates oral submucous fibrosis through inhibiting fibroblast-myofibroblast transition.

BACKGROUND: circRNAs have been shown to participate in diverse diseases; however, their role in oral submucous fibrosis (OSF), a potentially malignant disorder, remains obscure. Our preliminary experiments detected the expression of circRNA mitochondrial translation optimization 1 homologue (circMTO1) in OSF tissues (n = 20) and normal mucosa tissues (n = 20) collected from Hunan Xiangya Stomatological Hospital, and a significant decrease of circMTO1 expression was showed in OSF tissues. Therefore, we further explored circMTO1 expression in OSF. METHODS: Target molecule expression was detected using RT-qPCR and western blotting. The migration and invasion of buccal mucosal fibroblasts (BMFs) were assessed using wound healing and Transwell assays. The interaction between miR-30c-5p, circMTO1, and SOCS3 was evaluated using dual luciferase, RNA immunoprecipitation (RIP), and RNA pull-down assays. The colocalisation of circMTO1 and miR-30c-5p was observed using fluorescence in situ hybridisation (FISH). RESULTS: circMTO1 and SOCS3 expression decreased, whereas miR-30c-5p expression increased in patients with OSF and arecoline-stimulated BMFs. Overexpression of circMTO1 effectively restrained the fibroblast-myofibroblast transition (FMT), as evidenced by the increase in expression of Coll I, α-SMA, Vimentin, and the weakened migration and invasion functions in BMFs. Mechanistic studies have shown that circMTO1 suppresses FMT by enhancing SOCS3 expression by sponging miR-30c-5p and subsequently inactivating the FAK/PI3K/AKT pathway. FMT induced by SOCS3 silencing was reversed by the FAK inhibitor TAE226 or the PI3K inhibitor LY294002. CONCLUSION: circMTO1/miR-30c-5p/SOCS3 axis regulates FMT in arecoline-treated BMFs via the FAK/PI3K/AKT pathway. Expanding the sample size and in vivo validation could further elucidate their potential as therapeutic targets for OSF.

Polycomb repressive complex 2 and its core component EZH2: potential targeted therapeutic strategies for head and neck squamous cell carcinoma.

The polycomb group (PcG) comprises a set of proteins that exert epigenetic regulatory effects and play crucial roles in diverse biological processes, ranging from pluripotency and development to carcinogenesis. Among these proteins, enhancer of zeste homolog 2 (EZH2) stands out as a catalytic component of polycomb repressive complex 2 (PRC2), which plays a role in regulating the expression of homologous (Hox) genes and initial stages of x chromosome inactivation. In numerous human cancers, including head and neck squamous cell carcinoma (HNSCC), EZH2 is frequently overexpressed or activated and has been identified as a negative prognostic factor. Notably, EZH2 emerges as a significant gene involved in regulating the STAT3/HOTAIR axis, influencing HNSCC proliferation, differentiation, and promoting metastasis by modulating related oncogenes in oral cancer. Currently, various small molecule compounds have been developed as inhibitors specifically targeting EZH2 and have gained approval for treating refractory tumors. In this review, we delve into the epigenetic regulation mediated by EZH2/PRC2 in HNSCC, with a specific focus on exploring the potential roles and mechanisms of EZH2, its crucial contribution to targeted drug therapy, and its association with cancer markers and epithelial-mesenchymal transition. Furthermore, we aim to unravel its potential as a therapeutic strategy for oral squamous cell carcinoma.

Prognostic model revealing pyroptosis-related signatures in oral squamous cell carcinoma based on bioinformatics analysis.

One of the most common oral carcinomas is oral squamous cell carcinoma (OSCC), bringing a heavy burden to global health. Although progresses have been made in the intervention of OSCC, 5 years survival of patients suffering from OSCC is poor like before regarding to the high invasiveness of OSCC, which causes metastasis and recurrence of the tumor. The relationship between pyroptosis and OSCC remains to be further investigated as pyroptosis in carcinomas has gained much attention. Herein, the key pyroptosis-related genes were identified according to The Cancer Genome Atlas (TCGA) dataset. Additionally, a prognostic model was constructed based upon three key genes (CTLA4, CD5, and IL12RB2) through least absolute shrinkage and selection operator (LASSO) analyses, as well as univariate and multivariate COX regression in OSCC. It was discovered that the high expression of these three genes was associated with the low-risk group. We also identified LAIR2 as a hub gene, whose expression negatively correlated with the risk score and the different immune cell infiltration. Finally, we proved that these three genes were independent prognostic factors linked to overall survival (OS), and reliable consequences could be predicted by this model. Our study revealed the relationship between pyroptosis and OSCC, providing insights into new treatment targets for preventing and treating OSCC.

The Implication of Diabetes-Specialized Nurses in Aiming for the Better Treatment and Management of Patients with Diabetes Mellitus: A Brief Narrative Review.

Diabetes mellitus (DM) is regarded as one of the most critical public health challenges of the 21st century. It has evolved into a burgeoning epidemic since the last century, and today ranks among the major causes of mortality worldwide. Diabetes specialist nurses (DSNs) are central to good patient care and outcomes including confident self-care management. Evidence shows that DSNs are cost-effective, improve clinical outcomes, and reduce length of stay in hospital. In this brief narrative review, we aim to describe the roles of DSNs and their contribution in the treatment and management of patients with DM. This narrative review describes the importance of DSNs in healthcare practice, in the inpatient and outpatient departments, in the pediatrics department, in managing diabetic foot ulcers, in the treatment and management of gestational diabetes, in prescribing medications for DM and in diabetes self-management education on glycosylated hemoglobin, and cardiovascular risk factors. To conclude, DSNs have a crucial role in the treatment and management of patients with DM and its complications. DSNs have a great impact on diabetes therapy, and hence implementation of DSNs and nurse-led diabetic clinics might be beneficial for the health care system. Finally, having DSNs might significantly contribute to good healthcare practice and support. Even though DSNs are not available in several regions around the globe, and even though this post is still new to several health care institutions, the presence of DSNs recognized and certified by the various healthcare systems would be very useful.

Molecular basis, potential biomarkers, and future prospects of OSCC and PD-1/PD-L1 related immunotherapy methods.

Oral squamous cell carcinoma (OSCC) affects a large number of individuals worldwide. Despite advancements in surgery, radiation, and chemotherapy, satisfactory outcomes have not been achieved. In recent years, the success of drugs targeting programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) has led to breakthroughs in cancer treatment, but systematic summaries on their effectiveness against OSCC are lacking. This article reviews the latest research on the PD-1/PD-L1 pathway and the potential of combination therapy based on this pathway in OSCC. Further, it explores the mechanisms involved in the interaction of this pathway with exosomes and protein-protein interactions, and concludes with potential future OSCC therapeutic strategies.

Mechanisms and markers of malignant transformation of oral submucous fibrosis.

Oral submucous fibrosis (OSF) is a chronic premalignant disease associated with betel quid chewing. Epidemiological studies indicate that there are approximately 5 million individuals suffering from OSF worldwide, with a concerning malignancy transformation rate of up to 4.2 %. When OSF progresses to oral squamous cell carcinoma (OSCC), the 5-year survival rate for OSCC drops to below 60 %. Therefore, early screening and diagnosis are essential for both preventing and effectively treating OSF and its potential malignant transformation. Numerous studies have shown that the malignant transformation of OSF is associated with various factors, including epigenetic reprogramming, epithelial-mesenchymal transition, hypoxia, cell cycle changes, immune regulation disturbances, and oxidative damage. This review article focuses on the unraveling the potential mechanisms underlying the malignant transformation of OSF, as well as the abnormal expression of biomarkers throughout this transformative process, with the aim of aiding early screening for carcinogenic changes in OSF. Furthermore, we discuss the significance of utilizing blood and saliva components from patients with OSF, along with optical diagnostic techniques, in the early screening of OSF malignant transformation.

Osteonecrosis of the jaw induced by arsenic trioxide therapy in acute promyelocytic leukemia patient: a case report and literature review / 口腔疾病防治

Objective @#To investigate the etiology, clinical manifestations, treatment and prevention of jaw necrosis caused by arsenic trioxide to provide a reference for clinical diagnosis and treatment. @*Methods@#To analyze the clinical data and related literature of patients with jaw necrosis caused by acute promyelocytic leukemia treated with arsenic trioxide@*Results@#We report a case of jaw necrosis caused by the use of arsenic trioxide (10 mg once a day for one month) during the treatment of acute promyelocytic leukemia. About 20 days after treatment, the patient developed right maxillary pain accompanied by gingival redness and swelling and mucosal ulcer, 14-17 teeth had buccal and palatal alveolar bone exposed, gingival mucosa was missing, gingival tissue was damaged to the bottom of vestibular groove, and palatal soft tissue was damaged to 5-8 mm of palatal suture. Due to the unstable condition of acute promyelocytic leukemia, the patient was given conservative treatment such as oral vitamin and Kangfuxin liquid gargle to keep his mouth clean. Drug induced jaw necrosis reported in the literature can be caused by bisphosphonates. Arsenic trioxide can also cause local jaw necrosis. Clinically, it is often manifested as long-term wound nonunion, pus, alveolar bone or jaw bone exposure, dead bone formation, accompanied by pain, loose teeth, facial swelling and other symptoms. Anti inflammation, debridement and surgical removal of dead bone are commonly used treatment methods.@*Conclusion @# In clinical practice, we should be alert to drug-induced jaw necrosis and strengthen prevention.

Accuracy analysis of MRI in the depth of invasion assessment of tongue squamous cell carcinoma / 口腔疾病防治

Objective @#To analyze the accuracy of the infiltrating depth of tongue squamous cell carcinoma measured by magnetic resonance imaging (MRI) using pathological sections under a light microscope to provide a clinical reference.@*Methods @#Seventy-three patients with tongue squamous cell carcinoma who visited the Department of Stomatology of the First Hospital of Shanxi Medical University and Xiangya Stomatological Hospital from January 2018 to September 2020 were selected. Preoperative MRI was performed to evaluate the infiltration depth of tongue squamous cell carcinoma, and intraoperative frozen pathological sections were used to confirm the infiltration depth of tongue squamous cell carcinoma measurement. @*Results @#The infiltration depth of tongue squamous cell carcinoma measured by T1-weighted imaging was 1.11 mm (95% CI=0.51-1.70; t=3.72; P < 0.001), and the correlation coefficient r was 0.95. The T2-weighted average overestimation was 2.17 mm (95% CI=1.32-3.02; t=5.10; P < 0.001), and the correlation coefficient was 0.92. The Bland-Altman plot showed good consistency between T1- and T2-weighted images and pathologic measurements.@*Conclusion @#The infiltration depth of tongue squamous cell carcinoma measured by MRI is more accurate, with an average overestimation of 1-2 mm compared with pathological measurements, and T1-weighted images are better than T2-weighted images.

Effect of arecoline on SD rat survival after buccal mucosal biopsy / 口腔疾病防治

Objective @#To provide an experimental basis for predicting the sample size needed for animal experiments by studying the survival of SD rats after buccal mucosal biopsy with arecoline administered at different concentrations with different methods.@*Methods @#In all, 48 rats were divided into 8 groups, with 6 in each group, as follows: rats in groups A-D were treated with arecoline at different concentrations (0, 0.5, 2, 8 mg/mL); rats in groups E-H were treated with arecoline at different concentrations (0, 0.5, 2, 8 mg/mL), followed by stimulation of the buccal mucosa by mechanical rubbing. After 16 weeks, a 6-mm-diameter sample of the buccal mucosa was collected, and the wound was closed with interrupted sutures. The survival time of the rats was recorded, and the relationship between the survival time and the concentration of arecoline and mechanical stimulation was analyzed. @*Results@#No rats died during the first 16 weeks after treatment or after biopsy. The success rate of the arecoline stimulation model was 66.7%. The average observation time of all SD rats after biopsy was 42.5 days. Up to 120 days after biopsy, the cumulative survival rate in the eight groups was 50%, 33%, 17%, 0%, 33%, 17%, 0% and 0%, respectively (in alphabetical order). The cumulative survival rate in the groups administered 0 mg/mL (groups A and E), 0.5 mg/mL (groups B and F), 2 mg/mL (groups C and G), and 8 mg/mL (groups D and H) was 42%, 25%, 8% and 0%, respectively. Cox survival analysis showed that moderate and high concentrations of arecoline (2, 8 mg/mL) significantly affected the survival duration (P < 0.05), while mechanical stimulation had no significant effect on the survival duration (P > 0.05). The chi-squared test showed that the survival rate of rats showing wound healing (33.3%) was significantly higher than that of rats showing incomplete wound healing (0.0%) (P=0.003). @*Conclusion @#The success rate of the rat buccal submucosal fibrosis model was higher than moderate and high concentrations of arecoline, but the survival duration was significantly reduced after biopsy. Mechanical stimulation did not lead to a significant decrease in the survival duration, and impaired wound healing may be a cause of death in this model.

White sponge nevus: a case report and literature review / 口腔疾病防治

Objective@#To explore the etiology, clinical manifestation, diagnosis and treatment of white spongy spot nevus, so as to provide reference for clinical diagnosis and treatment. @*Methods @#The clinical data and related literature of a case of white cavernous nevus in oral cavity were retrospectively analyzed.@*Results @#White spongy nevus is a rare autosomal dominant hereditary disease with a family history. The mutations of keratin gene K4 and K13 in patients with white spongy nevus are considered to be the main causes. The disease usually starts in children and adolescents and tends to be stable in adulthood. It is characterized by extensive white water-wave folds on the mucosa, soft texture, and affects the bilateral buccal mucosa. Pathological examination usually shows excessive keratosis of epithelial cells, edema and vacuolation in spinous cells, while basal cells are generally normal. In clinic, it should be differentiated from oral leukoplakia, oral lichen planus and oral candidiasis. At present, there is no specific treatment method. Retinoic acid is often applied locally and gargle is used to keep oral hygiene and cleanliness. Patients can not be treated without conscious symptoms. The prognosis of the disease is good and there is no tendency of malignancy.@*Conclusion @#White spongy nevus is very rare and easily missed by clinicians. Diagnosis mainly depends on medical history, clinical manifestations and pathological examination. Future research directions should be devoted to finding more effective treatment.

Research progress on the CD4 +T cell balance in oral cancer and precancerous diseases / 口腔疾病防治

@#CD4 +T cells play an important role in regulating adaptive immune responses to various inflammatory responses. Parental T cell populations can differentiate in response to different cytokines into at least four subpopulations: Th1, Th2, Th17, and Treg cells. These differentiated T cells participate in various immune responses and have different roles and functions in oral cancer and precancerous diseases. The Th1/Th2 balance, the Th17/Treg balance and the occurrence and development of oral cancer and precancerous diseases are related to immune imbalances. Reversing these T cell imbalances and strengthening the patient’s autoimmune function may prevent or even reverse the progression of oral and precancerous diseases. This paper reviews the research advances on the CD4 +T cell balance in oral cancer and precancerous lesions.