Objective: Squamous cell carcinomas (SCCs) with shared etiology, histological characteristics, and certain risk factors represent the most common solid cancers. This study reports the crosstalk between autophagy and ferroptosis at the molecular level in SCCs, and their roles on the immunological tumor microenvironment (TME) of SCCs.Methods: In this study, the connections between autophagy and ferroptosis were characterized in SCCs by analyzing the associations between autophagy- and ferroptosis-related genes in mRNA expression and prognosis, protein-protein interactions and shared signaling pathways. Autophagy potential index (API) and ferroptosis potential index (FPI) of each tumor were quantified for reflecting autophagy and ferroptosis levels via principal-component analysis algorithm. Their synergistical roles on TME, immunity, drug resistance and survival were systematically analyzed in SCCs.Results: There were close connections between autophagy and ferroptosis at the mRNA and protein levels and prognosis. Both shared cancer-related pathways. The API and FPI were separately developed based on prognostic autophagy- and ferroptosis-related genes. A high correlation between API and FPI was found in SCCs. Their interplay was distinctly associated with favorable prognosis, enhanced sensitivity to chemotherapy drugs (Sunitinib, Gefitinib, Vinblastine and Vorinostat), an inflamed TME and higher likelihood of response to immunotherapy in SCCs.Conclusion: This study is the first to provide a comprehensive analysis of the interplay between autophagy and ferroptosis and their synergistical roles on manipulating the immunological TME in SCCs. These findings indicated that the induction of autophagy and ferroptosis combined with immunotherapy might produce synergistically enhanced anti-SCCs activity.

Background: The link between the gut microbiota (GM) and Sjögren’s Syndrome (SS) is well-established and apparent. Whether GM is causally associated with SS is uncertain.Methods: The MiBioGen consortium’s biggest available genome-wide association study (GWAS) meta-analysis (n=13,266) was used as the basis for a two-sample Mendelian randomization study (TSMR). The causal relationship between GM and SS was investigated using the inverse variance weighted, MR-Egger, weighted median, weighted model, MR-PRESSO, and simple model methods. In order to measure the heterogeneity of instrumental variables (IVs), Cochran’s Q statistics were utilized.Results: The results showed that genus Fusicatenibacter (odds ratio (OR) = 1.418, 95% confidence interval (CI), 1.072–1.874, P = 0.0143) and genus Ruminiclostridium9 (OR = 1.677, 95% CI, 1.050–2.678, P = 0.0306) were positively correlated with the risk of SS and family Porphyromonadaceae (OR = 0.651, 95% CI, 0.427–0.994, P = 0.0466), genus Subdoligranulum (OR = 0.685, 95% CI, 0.497–0.945, P = 0.0211), genus Butyricicoccus (OR = 0.674, 95% CI, 0.470–0.967, P = 0.0319) and genus Lachnospiraceae (OR = 0.750, 95% CI, 0.585–0.961, P = 0.0229) were negatively correlated with SS risk using the inverse variance weighted (IVW) technique. Furthermore, four GM related genes: ARAP3, NMUR1, TEC and SIRPD were significant causally with SS after FDR correction (FDR<0.05).Conclusions: This study provides evidence for either positive or negative causal effects of GM composition and its related genes on SS risk. We want to provide novel approaches for continued GM and SS-related research and therapy by elucidating the genetic relationship between GM and SS.

Objective: This study aimed to systematically investigate and compare the post-treatment recurrence of intraosseous ameloblastoma in patients treated with conservative or aggressive approaches. Methods: Systemic searches of PubMed, Medline, Cochrane Library, and Embase databases from inception to October 28, 2020, were conducted. Studies that aimed to evaluate the recurrence of intraosseous ameloblastoma by conservative and aggressive treatment approaches were included. Results: A total of 20 studies with 942 ameloblastoma cases were included. Fourteen studies included patients with ameloblastoma who received conservative treatment, and 16 studies reported the overall recurrence rate for patients undergoing aggressive treatment. The pooled results indicated that the recurrence rate for aggressive treatment [0.12, 95% confidence interval (CI) = 0.09–0.16] was significantly lower than that for conservative treatment, with a recurrence rate of 0.30 (95% CI = 0.23–0.39). Similar results were obtained when stratifying the participants by the histological classification. When trying stratification analysis following the original included studies, multicystic ameloblastoma presented a much higher recurrence rate than solid and unicystic ameloblastomas. Conclusion: These findings supported the hypothesis that aggressive treatment might lead to a lower recurrence rate than conservative treatment. More studies and meta-analyses following the new histological classification of ameloblastomas are needed to validate and support the findings.

Objective: To comprehensively analyze the global N⁶-methyladenosine (m⁶A) modification pattern in ameloblastoma. Methods: m⁶A peaks in ameloblastoma and normal oral tissues were detected by MeRIP-seq. Differentially methylated m⁶A sites within messenger RNAs (mRNAs), long no-coding RNA (lncRNAs) and circular RNA (circRNAs) were identified, followed by functional enrichment analysis. By comprehensively analyzing MeRIP-seq and RNA-seq data, differentially expressed mRNAs, lncRNAs and circRNAs containing differentially methylated sites were identified. RNA binding proteins (RBPs) were then identified for differentially methylated m⁶A sites. Results: In total, 3,673 differentially methylated m⁶A sites within coding genes were detected, of which 16.2% (704/3,673) were significantly upmethylated sites in ameloblastoma compared to normal oral tissues. Furthermore, 4,975 differentially methylated m⁶A sites within lncRNAs were identified, of which 29.4% (1,465/4,975) were upmethylated sites in ameloblastoma. We also found 364 differentially methylated m⁶A sites within circRNAs, of which 22.5% (82/364) were upmethylated sites in ameloblastoma. Differentially methylated m⁶A was most often harbored in the CDS (54.10%), followed by 5’UTR (21.71%). Functional enrichment analysis revealed that m⁶A modification could be involved in the development of ameloblastoma by organism developmental processes. A total of 158 RBPs within differentially methylated m⁶A sites were identified, which were significantly involved in mRNA metabolic process, mRNA processing, RNA processing, RNA splicing and RNA transport. Conclusion: Our findings for the first time provide m⁶A landscape of human ameloblastoma, which expand the understanding of m⁶A modifications and uncover regulation of lncRNAs and circRNAs through m⁶A modification in ameloblastoma.

Serum response factor (SRF) regulates pro-carcinogenic genes in various cancers, but its role in oral squamous cell carcinoma (OSCC) remains unclear. SRF expression in 70 OSCC samples was detected via immunohistochemistry. Abundant SRF expressed in OSCC tissues was closely associated with tumor metastasis. SRF-overexpressing OSCC cells were constructed to evaluate how SRF affects OSCC cell tumorigenesis and epithelial-to-mesenchymal transition (EMT) in vitro and in vivo. Overexpressed SRF increased OSCC cell migration and invasion in vitro and tumor growth and invasion in vivo. This promoted EMT, characterized by decreased and increased expression of E- and N-cadherin, respectively. Furthermore, an analysis of RNA sequences of transcriptional targets of SRF showed that SRF transactivated the indoleamine 2, 3-dioxygenase 1 (IDO1)/kynurenine-aryl hydrocarbon receptor (Kyn-AhR) signaling pathway in OSCC cell lines. Direct SRF binding to the IDO1 gene promoter upregulated transcription, which was detected through chromatin immunoprecipitation and dual luciferase reporter assays. Inhibiting IDO1 or AhR impaired SRF-induced migration and invasion and prevented EMT in OSCC cells. Our results demonstrated that SRF is a critical regulator of the IDO1/Kyn-AhR signaling pathway. This in turn increases OSCC cell migration and invasion by modulating EMT, which, consequently, favors OSCC cell growth and metastasis. We revealed a novel molecular mechanism through which SRF modulates OSCC metastasis. This should provide potential targets or biomarkers for OSCC diagnosis and treatment.