Effect of mutation at c.493T>C locus of transcription factor HNF1α gene on its protein level.

Hepatocyte nuclear factor 1α (HNF1α) is a transcription factor that is crucial for the regulation to maintain the function of pancreatic ß-cell, hepatic lipid metabolism, and other processes. Mature-onset diabetes of the young type 3 is a monogenic form of diabetes caused by HNF1α mutations. Although several mutation sites have been reported, the specific mechanisms remain unclear, such hot-spot mutation as the P291fsinsC mutation and the P112L mutation and so on. In preliminary studies, we discovered one MODY3 patient carrying a mutation at the c.493T>C locus of the HNF1α gene. In this study, we analyzed the pathogenic of the mutation sites by using the Mutation Surveyor software and constructed the eukaryotic expression plasmids of the wild-type and mutant type of HNF1α to detect variations in the expression levels and stability of HNF1α protein by using Western blot. The analyses of the Mutation Surveyor software showed that the c.493T>C site mutation may be pathogenic gene and the results of Western blot showed that both the amount and stability of HNF1α protein expressed by the mutation type plasmid were reduced significantly compared to those by the wild type plasmid (P<0.05). This study suggests that the c.493T>C (p.Trp165Arg) mutation dramatically impacts HNF1α expression, which might be responsible for the development of the disease and offers fresh perspectives for the following in-depth exploration of MODY3's molecular pathogenic process.

Diagnostic performance of contrast-enhanced mammography for suspicious findings in dense breasts: A systematic review and meta-analysis.

PURPOSE: Contrast-enhanced spectral imaging (CEM) is a new mammography technique, but its diagnostic value in dense breasts is still inconclusive. We did a systematic review and meta-analysis of studies evaluating the diagnostic performance of CEM for suspicious findings in dense breasts. MATERIALS AND METHODS: The PubMed, Embase, and Cochrane Library databases were searched systematically until August 6, 2023. Prospective and retrospective studies were included to evaluate the diagnostic performance of CEM for suspicious findings in dense breasts. The QUADAS-2 tool was used to evaluate the quality and risk of bias of the included studies. STATA V.16.0 and Review Manager V.5.3 were used to meta-analyze the included studies. RESULTS: A total of 10 studies (827 patients, 958 lesions) were included. These 10 studies reported the diagnostic performance of CEM for the workup of suspicious lesions in patients with dense breasts. The summary sensitivity and summary specificity were 0.95 (95% CI, 0.92-0.97) and 0.81 (95% CI, 0.70-0.89), respectively. Enhanced lesions, circumscribed margins, and malignancy were statistically correlated. The relative malignancy OR value of the enhanced lesions was 28.11 (95% CI, 6.84-115.48). The relative malignancy OR value of circumscribed margins was 0.17 (95% CI, 0.07-0.45). CONCLUSION: CEM has high diagnostic performance in the workup of suspicious findings in dense breasts, and when lesions are enhanced and have irregular margins, they are often malignant.

Multi-omics analysis provides new insights into the changes of important nutrients and fructose metabolism in loquat bud sport mutant.

Bud sport is a common and stable somatic variation in perennial fruit trees, and often leads to significant modification of fruit traits and affects the breeding value. To investigate the impact of bud sport on the main metabolites in the fruit of white-fleshed loquat, we conducted a multi-omics analysis of loquat fruits at different developmental stages of a white-fleshed bud sport mutant of Dongting loquat (TBW) and its wild type (TBY). The findings from the detection of main fruit quality indices and metabolites suggested that bud sport resulted in a reduction in the accumulation of carotenoids, fructose, titratable acid and terpenoids at the mature stage of TBW, while leading to the accumulation of flavonoids, phenolic acids, amino acids and lipids. The comparably low content of titratable acid further enhances the balanced and pleasent taste profile of TBW. Expression patterns of differentially expressed genes involved in fructose metabolism exhibited a significant increase in the expression level of S6PDH (EVM0006243, EVM0044405) prior to fruit maturation. The comparison of protein sequences and promoter region of S6PDH between TBY and TBW revealed no structural variations that would impact gene function or expression, indicating that transcription factors may be responsible for the rapid up-regulation of S6PDH before maturation. Furthermore, correlation analysis helped to construct a comprehensive regulatory network of fructose metabolism in loquat, including 23 transcription factors, six structural genes, and nine saccharides. Based on the regulatory network and existing studies, it could be inferred that transcription factors such as ERF, NAC, MYB, GRAS, and bZIP may promote fructose accumulation in loquat flesh by positively regulating S6PDH. These findings improve our understanding of the nutritional value and breeding potential of white-fleshed loquat bud sport mutant, as well as serve as a foundation for exploring the genes and transcription factors that regulate fructose metabolism in loquat.

Evaluating the influence of sarcopenia and myosteatosis on clinical outcomes in gastric cancer patients undergoing immune checkpoint inhibitor.

BACKGROUND: The development and progression of gastric cancer (GC) are closely linked to the nutritional status of patients. Although immunotherapy has been demonstrated to be clinically effective, the relationships of sarcopenia and myosteatosis with the use of immune checkpoint inhibitors (ICIs) in patients with gastric cancer remain to be characterized. AIM: To assess the effects of sarcopenia and myosteatosis on the clinical outcomes of patients with GC undergoing treatment with an ICI. METHODS: We performed a retrospective study of patients who were undergoing immunotherapy for GC. For the evaluation of sarcopenia, the optimal cut-off value for the skeletal muscle index was established using receiver operating characteristic analysis of data obtained from pre-treatment computed tomography images at the L3 vertebral level. Myosteatosis was defined using the mean skeletal muscle density (SMD), with a threshold value of < 41 Hounsfield units (HU) for patients with a body mass index (BMI) < 25 kg/m² and < 33 HU for those with a BMI ≥ 25 kg/m². The log-rank test was used to compare progression-free survival (PFS) and overall survival (OS), and a Cox proportional hazard model was used to identify prognostic factors. Nomograms were developed to predict the PFS and OS of patients on the basis of the results of multivariate analyses. RESULTS: We studied 115 patients who were undergoing ICI therapy for GC, of whom 27.4% had sarcopenia and 29.8% had myosteatosis. Patients with sarcopenia or myosteatosis had significantly shorter PFS and OS than those without these conditions. Furthermore, both sarcopenia and myosteatosis were found to be independent predictors of PFS and OS in patients with GC administering an ICI. The prediction models created for PFS and OS were associated with C-indexes of 0.758 and 0.781, respectively. CONCLUSION: The presence of sarcopenia or myosteatosis is a reliable predictor of the clinical outcomes of patients with GC who are undergoing treatment with an ICI.

High serum uric acid is a risk factor for arterial stiffness in a Chinese hypertensive population: a cohort study.

The prospective cohort study was to explore the association between serum uric acid (SUA) and arterial stiffness in a Chinese hypertensive population. A total of 7444 participants with hypertension who completed two or more measurements of brachial-ankle pulse wave velocity (baPWV) and baseline SUA detection were followed-up in the Kailuan Study from 2010 to 2020. A restricted cubic spline curve was used to verify whether there was a linear association between baseline SUA and arterial stiffness. A Cox proportional hazard regression model was used to explore the association of between baseline SUA and the incidence of arterial stiffness. Our results showed that the restricted cubic spline curve revealed a linear relationship between baseline SUA and arterial stiffness in total participants (p < 0.001). After follow-up 4.6 ± 2.8 years, Kaplan-Meier survival curves indicated that the risk of arterial stiffness was increased in the high level of baseline SUA (Log-rank p = 0.0002). After adjusting for potential confounding factors, the HR (95% CI) for risk of stiffness was 1.33 (1.17-1.52, p < 0.001) in the highest SUA group. Hierarchical analysis showed that the HRs (95% CI) for risk of arterial stiffness were 1.45 (1.25-1.69), 1.38 (1.19-1.60), 1.41 (1.21-1.64), and 1.35 (1.15-1.58) in the highest SUA group of males, <65 years old, not taking antihypertensive drugs, and failure to achieve the control targets of blood pressure respectively (p < 0.001). These results reveal that high SUA is a risk factor for arterial stiffness in the Chinese hypertensive population.

Relationship between resting heart rate and long-term outcomes in stabilized patients with myocardial infarction: A prospective community-based cohort study.

BACKGROUND: Resting heart rate (RHR) during hospitalization has been shown to be associated with adverse outcomes in patients with myocardial infarction (MI). This study aimed to evaluate the long-term prognostic effect of RHR during the stable phase after MI in post-MI patients. METHODS: Patients who had prior or new-onset MI and RHR measurements during the stable period after MI between 2006 and 2018 in the community-based Kailuan Study were enrolled. RHR was divided into four groups based on quartiles. Cox regression analysis was used to analyze the association of RHR with primary composite outcome of all-cause death, hospitalization for heart failure (HF), stroke, and recurrent MI and its components. RESULTS: A total of 4447 post-MI patients were included. During a median follow-up of 7.5 years, 1813 patients (40.8%) developed primary outcomes. Compared to RHR ≤67 bpm, patients with 72 < RHR ≤80 bpm and RHR >80 bpm had increased risks of primary outcome, with adjusted hazard ratios (95% confidence intervals) of 1.23 (1.08-1.40) and 1.35 (1.18-1.55), respectively. The risk of primary outcome increased by 12% (1.07-1.17) for each 10-bpm increase in RHR. Similar results were observed in all-cause death and hospitalization for HF. Restricted cubic splines revealed a linear relationship between RHR and primary outcome, all-cause death, and hospitalization for HF (P for nonlinearity >0.05). CONCLUSIONS: RHR during the stable phase after MI was an independent predictor for primary outcome and all-cause death in post-MI patients, and RHR >72 bpm was associated with increased risk for primary outcome and all-cause death.

Hypertension combined with atherosclerosis increases the risk of heart failure in patients with diabetes.

The increase in heart failure risk in the diabetic population when hypertension and atherosclerosis are both present is still inconclusive. The aim of this study was to explore the effects of hypertension combined with atherosclerosis in diabetic population on the risk of heart failure. We selected 10,711 patients with diabetes who participated in the Kailuan study and completed brachial-ankle pulse wave velocity (baPWV) testing for statistical analysis. The subjects were divided into the non-hypertensive non-atherosclerotic, hypertensive, atherosclerotic, and hypertensive atherosclerotic groups based on their history of hypertension and atherosclerosis. At a median follow-up of 4.15 years, 227 cases of heart failure occurred. Compared with the non-hypertensive non-atherosclerotic group, the multifactorial Cox proportional risk regression model showed that the hazard ratio (HR) for heart failure in the hypertensive atherosclerotic group was 3.08 (95% confidence interval [CI]: 1.32-7.16), whereas the HR decreased to 2.38 (95% CI: 1.01-5.63) after gradual correction of lipid-lowering, glucose-lowering, and antihypertensive drugs. The subgroup analysis and sensitivity analysis were consistent with that of total population. In conclusion, patients with diabetes exposed to both hypertension and atherosclerosis had an increased heart failure risk, which was attenuated by the use of lipid-lowering, glucose-lowering, and antihypertensive drugs.

Single-nucleus transcriptome sequencing reveals hepatic cell atlas in pigs.

BACKGROUND: As the largest substantive organ of animals, the liver plays an essential role in the physiological processes of digestive metabolism and immune defense. However, the cellular composition of the pig liver remains poorly understood. This investigation used single-nucleus RNA sequencing technology to identify cell types from liver tissues of pigs, providing a theoretical basis for further investigating liver cell types in pigs. RESULTS: The analysis revealed 13 cells clusters which were further identified 7 cell types including endothelial cells, T cells, hepatocytes, Kupffer cells, stellate cells, B cells, and cholangiocytes. The dominant cell types were endothelial cells, T cells and hepatocytes in the liver tissue of Dahe pigs and Dahe black pigs, which accounts for about 85.76% and 82.74%, respectively. The number of endothelial cells was higher in the liver tissue of Dahe pigs compared to Dahe black pigs, while the opposite tendency was observed for T cells. Moreover, functional enrichment analysis demonstrated that the differentially expressed genes in pig hepatic endothelial cells were significantly enriched in the protein processing in endoplasmic reticulum, MAPK signaling pathway, and FoxO signaling pathway. Functional enrichment analysis demonstrated that the differentially expressed genes in pig hepatic T cells were significantly enriched in the thyroid hormone signaling pathway, B cell receptor signaling pathway, and focal adhesion. Functional enrichment analysis demonstrated that the differentially expressed genes in pig hepatic hepatocytes were significantly enriched in the metabolic pathways. CONCLUSIONS: In summary, this study provides a comprehensive cell atlas of porcine hepatic tissue. The number, gene expression level and functional characteristics of each cell type in pig liver tissue varied between breeds.

Elevated high-sensitivity C-reactive protein levels increase the risk of new-onset cardiac conduction disorders.

BACKGROUND: Previous studies have reported that inflammatory responses can promote the onset of cardiovascular diseases; however, its association with cardiac conduction disorders remains unclear. The present community-based cohort study aimed to elucidate the effects of inflammatory responses on the risk of developing cardiac conduction disorders. METHODS: After the exclusion of participants failing to meet the inclusion criteria, 86,234 eligible participants (mean age: 50.57 ± 11.88 years) were included. The participants were divided into high-sensitivity C-reactive protein (hsCRP) ≤ 3 mg/L, and hsCRP > 3 mg/L groups based on hsCRP values. Multivariate Cox proportional hazard model was used to analyze the relationship between inflammatory responses and various cardiac conduction disorders. RESULTS: After adjusting for confounding factors, we observed that compared with the hsCRP ≤ 3 mg/L group, the hsCRP > 3 mg/L group exhibited increased risks of atrioventricular block (hazard ratio [HR]:1.64, 95%confidence interval [CI] 1.44-1.87) and left (HR:1.25, 95% CI 1.07-1.45) and right bundle branch block (HR:1.31, 95% CI 1.17-1.47). Moreover, the risk of various cardiac conduction disorders increased for every 1 standard deviation increase in log (hsCRP). The restricted cubic spline function confirmed a linear relationship between log (hsCRP) and the risk of developing cardiac conduction disorders (All nonlinearity P > 0.05). CONCLUSIONS: High hsCRP levels are an independent risk factor for cardiac conduction disorders, and hsCRP levels are dose-dependently associated with the risk of conduction disorders. Our study results may provide new strategies for preventing cardiac conduction disorders.

Comparisons of drug-eluting balloon versus drug-eluting stent for the treatment of cancer patients presenting with acute myocardial infarction.

BACKGROUND: Treatment for cancer patients presenting with acute myocardial infarction (AMI) remains challenging. The objective of the study was to investigate the safety and efficiency of drug eluting balloon (DEB) versus drug eluting stent (DES) in this high-risk group. METHODS: Between 1st January 2017 and 1st January 2022, cancer patients admitted to Beijing Chaoyang Hospital with AMI were retrospectively enrolled. The primary endpoint was major adverse cardiovascular event (MACE). The secondary endpoints included major bleeding events, heart failure and cardiac complications. RESULTS: A total of 164 cancer patients presenting with AMI were included in the final analysis. Patients treated with DEB had a numerically lower rate of MACE than those treated with DES during a median follow-up of 21.8 months (22.9% vs. 37.1%, p = 0.23). Patients treated with DEB had a trend towards lower rate of major bleeding events than patients treated with DES (6.3% vs. 18.1%, HR 2.96, 95% CI [0.88, 9.92], p = 0.08). There were no significant differences between the two groups with regards to the rate of heart failure (4.2% vs. 9.5%, p = 0.32) and cardiac complications (0.0% vs. 2.6%, p = 0.56). CONCLUSIONS: The present study demonstrated that in cancer patients with AMI, DEB had a trend towards lower rate of major bleeding events and a numerically lower rate of MACE compared with DES.

COVID-19 Associated Myocarditis: Prevalence, Pathophysiology, Diagnosis, and Management.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a pandemic and affected public health greatly. While COVID-19 primarily damages the lungs, leading to cough, sore throat, pneumonia, or acute respiratory distress syndrome, it also infects other organs and tissues, including the cardiovascular system. In particular, myocarditis is a well-recognized severe complication of COVID-19 infection and could result in adverse outcomes. Angiotensin-Converting Enzyme2 is thought to play a pivotal role in SARS-CoV-2 infection, and immune overresponse causes overwhelming damage to the host's myocardium. Direct viral infection and injury do take a part as well, but more evidence is needed to strengthen this proposal. The clinical abnormalities include elevated cardiac biomarkers and electrocardiogram changes and impaired cardiac function that might be presented in echocardiography and cardiovascular magnetic resonance imaging. If necessary, the endomyocardial biopsy would give more forceful information to diagnosis and aid in treatment. Comparisons between COVID-19 myocarditis and other viral myocarditis are also discussed briefly.

Enhancer-driven transcription of MCM8 by E2F4 promotes ATR pathway activation and glioma stem cell characteristics.

BACKGROUND: Glioma stem cells (GSCs) are responsible for glioma recurrence and drug resistance, yet the mechanisms underlying their maintenance remains unclear. This study aimed to identify enhancer-controlled genes involved in GSCs maintenance and elucidate the mechanisms underlying their regulation. METHODS: We analyzed RNA-seq data and H3K27ac ChIP-seq data from GSE119776 to identify differentially expressed genes and enhancers, respectively. Gene Ontology analysis was performed for functional enrichment. Transcription factors were predicted using the Toolkit for Cistrome Data Browser. Prognostic analysis and gene expression correlation was conducted using the Chinese Glioma Genome Atlas (CGGA) data. Two GSC cell lines, GSC-A172 and GSC-U138MG, were isolated from A172 and U138MG cell lines. qRT-PCR was used to detect gene transcription levels. ChIP-qPCR was used to detect H3K27ac of enhancers, and binding of E2F4 to target gene enhancers. Western blot was used to analyze protein levels of p-ATR and γH2AX. Sphere formation, limiting dilution and cell growth assays were used to analyze GSCs growth and self-renewal. RESULTS: We found that upregulated genes in GSCs were associated with ataxia-telangiectasia-mutated-and-Rad3-related kinase (ATR) pathway activation, and that seven enhancer-controlled genes related to ATR pathway activation (LIN9, MCM8, CEP72, POLA1, DBF4, NDE1, and CDKN2C) were identified. Expression of these genes corresponded to poor prognosis in glioma patients. E2F4 was identified as a transcription factor that regulates enhancer-controlled genes related to the ATR pathway activation, with MCM8 having the highest hazard ratio among genes positively correlated with E2F4 expression. E2F4 bound to MCM8 enhancers to promote its transcription. Overexpression of MCM8 partially restored the inhibition of GSCs self-renewal, cell growth, and the ATR pathway activation caused by E2F4 knockdown. CONCLUSION: Our study demonstrated that E2F4-mediated enhancer activation of MCM8 promotes the ATR pathway activation and GSCs characteristics. These findings offer promising targets for the development of new therapies for gliomas.

Comparisons of different new-generation transcatheter aortic valve implantation devices for patients with severe aortic stenosis: a systematic review and network meta-analysis.

BACKGROUND: Whether there are differences among the new-generation transcatheter aortic valve implantation (TAVI) devices for patients with aortic stenosis remains unclear. The aim of the study was to compare the efficiency and safety of different new-generation TAVI devices for patients with aortic stenosis. MATERIALS AND METHODS: A comprehensive search of PubMed, Embase and Web of Science from their inception to 1 February 2022. Randomized clinical trials and observational studies that compared two or more different TAVI devices were enroled. Pairwise meta-analysis and frequentist network meta-analysis were conducted to pool the outcome estimates of interest. RESULTS: A total of 79 studies were finally included. According to the surface under the cumulative ranking, the top two ranked valves for lower rates of events were as follows: direct flow medical (DFM) (4.6%) and Lotus (48.8%) for lower rate of device success; Sapien 3 (16.8%) and DFM (19.7%) for lower mortality; DFM (8.6%) and Sapien 3 (25.5%) for lower rates of stroke; Evolut (27.6%) and DFM (35.8%) for lower rates of major and life-threatening bleeding; Portico (22.6%) and Sapien 3 (41.9%) for lower rates of acute kidney injury; Acurate (8.6%) and DFM (13.2%) for lower rates of permanent pacemaker implantation; Lotus (0.3%) and Sapien 3 (22.7%) for lower rates of paravalvular leak; Evolut (1.4%) and Portico (29.1%) for lower rates of mean aortic valve gradients. CONCLUSIONS: The findings of the present study suggested that the device success rates were comparable among these new-generation valves except for DFM. After excluding DFM, Sapien 3 might be the best effective for decreased mortality and stroke; Lotus might be the best effective for decreased paravalvular leak; Evolut might be the best effective for decreased major and life-threatening bleeding and mean aortic valve gradients; Acurate and Portico might be the best effective for decreased permanent pacemaker implantation and acute kidney injury, respectively.

Generation of stable integration-free pig induced pluripotent stem cells under chemically defined culture condition.

Genome integration-free pig induced pluripotent stem cells (iPSCs) bring tremendous value in pre-clinical testing of regenerative medicine, as well as conservation and exploitation of endangered or rare local pig idioplasmatic resources. However, due to a lack of appropriate culture medium, efficient induction and stable maintenance of pig iPSCs with practical value remains challenging. Here, we established an efficient induction system for exogenous gene-independent iPSCs under chemically defined culture condition previously used for generation of stable pig pre-gastrulation epiblast stem cells (pgEpiSCs). WNT suppression was found to play an essential role in establishment of exogenous gene-independent iPSCs. Strikingly, stable integration-free pig iPSCs could be established from pig somatic cells using episomal vectors in this culture condition. The iPSCs had pluripotency features and transcriptome characteristics approximating pgEpiSCs. More importantly, this induction system may be used to generate integration-free iPSCs from elderly disabled rare local pig somatic cells and the iPSCs could be gene-edited and used as donor cells for nuclear transfer. Our results provide novel insights into potential applications for genetic breeding of livestock species and pre-clinical evaluation of regenerative medicine.

Association between input/weight ratio and acute kidney injury in obese critical ill patients: a propensity analysis of multicenter clinical databases.

Rehydration volume may be underestimated in obese critically ill patients, which can lead to acute kidney injury (AKI). This study aimed to investigate the association between input/weight ratio (IWR) and AKI risk in obese critical patients. This retrospective observational study analyzed data from three large open databases. Patients were divided into lean and obese groups and matched 1:1 based on age, sex, APACHE II score, SOFA score, sepsis status, mechanical ventilation status, renal replacement therapy status, and hospital type. The exposure of interest was the mean IWR during the first three ICU admission days. The primary outcome was the incidence of AKI within 28 days after ICU admission. Cox regression analysis was used to evaluate the association between IWR and AKI risk. A total of 82,031 eligible patients were included in the study, with 25,427 obese patients matched with 25,427 lean patients. The IWRs were significantly lower in the obese groups in both the unmatched cohort (35.85 ± 19.05 vs. 46.01 ± 30.43 ml/kg, p < 0.01) and the matched cohort (36.13 ± 19.16 vs. 47.34 ± 31.13 ml/kg, p < 0.01). An increase in IWR was significantly associated with decreased creatinine levels, increased urine output and a lower AKI risk. The interaction terms of IWR and obesity were significantly associated with decreased AKI incidence in both the unmatched cohort (hazard ratio [HR] = 0.97, 95% CI 0.96-0.97, p < 0.01) and the matched cohort (HR = 0.97, 95% CI 0.96-0.97, p < 0.01). Inadequate rehydration of patients with obesity may contribute to an increased risk of AKI in patients with obesity. These results highlight the need for better rehydration management in patients with obesity.

Increased arterial stiffness elevates the risk of heart failure in diabetic patients.

BACKGROUND: Previous studies have shown that arterial stiffness (AS) was a risk factor for heart failure (HF) in nondiabetic patients. We aimed to analyze this impact in a community-based diabetic population. METHODS: Our study excluded those who had HF before brachial-ankle pulse wave velocity (baPWV) measurement and included 9041 participants finally. Subjects were divided into the normal (<14 m/s), intermediate (14-18 m/s), and elevated baPWV groups (>18 m/s) based on baPWV values. Multivariate Cox proportional hazard model was used to analyze the effect of AS on HF risk. RESULTS: During the median follow-up of 4.19 years, 213 patients had HF. The results of Cox model showed that HF risk in the elevated baPWV group was 2.25 times higher than that in the normal baPWV group (95% confidence interval [CI]: 1.24-4.11). HF risk increased by 18% (95% CI:1.03-1.35) for every 1 additional standard deviation(SD)of baPWV. Restricted cubic spline results showed statistically significant overall and non-linear associations between AS and HF risk (P < 0.05). The subgroup analysis and sensitivity analysis were consistent with that of total population. CONCLUSIONS: AS is an independent risk factor for developing HF in the diabetic population, and AS exhibits a dose-response relationship with HF risk.

Matrix stiffness induces an invasive-dormant subpopulation via cGAS-STING axis in oral cancer.

OBJECTIVES: Dormancy is a crucial machinery for cancer cells to survive hostile microenvironment. It is considered as the major cause of post-treatment relapse and metastases. However, its regulatory mechanism in oral squamous cell carcinoma (OSCC) remains unclear. Here we sought to decipher the impacts of matrix stiffness on OSCC-cell dormancy. MATERIALS AND METHODS: Clinicopathological relevance of matrix stiffness in OSCC was analyzed in a 127 patients' cohort. Impacts of stiffness-related mechanical stress (MS) on OSCC-cell behaviors were investigated in vitro and in vivo. Transcriptomic profiling of MS induced dormant cells were performed, following by mechanistic investigations on MS-induced dormancy. The functional relevance of cGAS in OSCC were analyzed through a bioinformatic approach. RESULTS: Stiffened matrix correlated with poor survival and post-surgical recurrence in OSCC. Stiffness-related MS induces a dormant subpopulation in OSCC cells, which showed increased drug resistance, enhanced tumor repopulating ability, and an unexpected upregulation of epithelial-mesenchymal transition (EMT) and invasiveness. Mechanistically, MS caused DNA damage, resulted in activation of cGAS-STING signaling. Either blocking of cGAS or STING dramatically impeded the MS-induced production of this invasive-dormant subpopulation. Moreover, cGAS was found being central to the cell-cycle regulation and correlated with poor prognosis in OSCC. DISCUSSION: We revealed a previously unsuspected role of cGAS-STING axis in mediating the induction of an invasive-dormant subpopulation in response to mechanical cues. Our findings indicated an adaptive machinery whereby tumor cells survive and escape from harsh microenvironment. Targeting this machinery may be a potential strategy for preventing post-therapeutic recurrence and lymphatic metastasis in OSCC.