Gastric cancer (GC) is one of the leading causes of cancer-related deaths and shows high levels of heterogeneity. The development of a specific prognostic model is important if we are to improve treatment strategies. Pyroptosis can arise in response to H. pylori, a primary carcinogen, and also in response to chemotherapy drugs. However, the prognostic evaluation of GC to pyroptosis is insufficient. Consensus clustering by pyroptosis-related regulators was used to classify 618 patients with GC from four GEO cohorts. Following Cox regression with differentially expressed genes, our prognosis model (PS-score) was built by LASSO-Cox analysis. The TCGA-STAD cohort was used as the validation set. ESTIMATE, CIBERSORTx, and EPIC were used to investigate the tumor microenvironment (TME). Immunotherapy cohorts by blocking PD1/PD-L1 were used to investigate the treatment response. The subtyping of GC based on pyroptosis-related regulators was able to classify patients according to different clinical traits and TME. The difference between the two subtypes identified in this study was used to develop a prognosis model which we named “PS-score.” The PS-score could predict the prognosis of patients with GC and his/her overall survival time. A low PS-score implies greater inflammatory cell infiltration and better response of immunotherapy by PD1/PD-L1 blockers. Our findings provide a foundation for future research targeting pyroptosis and its immune microenvironment to improve prognosis and responses to immunotherapy.

Chronic inflammation is the primary cause of gastric cancer (GC). NLRP3, as an important inflammasome component, has crucial roles in initiating inflammation. However, the potential roles of NLRP3 in GC is unknown. Here, we show that NLRP3 expression is markedly upregulated in GC, which promotes NLRP3 inflammasome activation and interleukin-1β (IL-1β) secretion in macrophages. In addition, NLRP3 binds to cyclin-D1 (CCND1) promoter and promotes its transcription in gastric epithelial cells. Consequently, NLRP3 enhances epithelial cells proliferation and GC tumorigenesis. Furthermore, we identify miR-22, which is constitutively expressed in gastric mucosa, as a suppressor of NLRP3. MiR-22 directly targets NLRP3 and attenuates its oncogenic effects in vitro and in vivo. However, Helicobacter pylori (H. pylori) infection suppresses miR-22 expression, while enhances NLRP3 expression, and that triggers uncontrolled proliferation of epithelial cells and the emergence of GC. Thus, our research describes a mechanism by which miR-22 suppresses NLRP3 and maintains homeostasis of gastric microenvironments and suggests miR-22 as a potential target for the intervention of GC.

The development of chemotherapy resistance is the most vital obstacle to clinical efficacy in gastric cancer (GC). The dysregulation of the Wnt/beta-catenin signaling pathway is critically associated with GC development and chemotherapy resistance. Ferroptosis is a form of regulated cell death, induced by an iron-dependent accumulation of lipid peroxides during chemotherapy. However, whether the Wnt/beta-catenin signaling directly controls resistance to cell death, remains unclear. Here, we show that the activation of the Wnt/beta-catenin signaling attenuates cellular lipid ROS production and subsequently inhibits ferroptosis in GC cells. The beta-catenin/TCF4 transcription complex directly binds to the promoter region of GPX4 and induces its expression, resulting in the suppression of ferroptotic cell death. Concordantly, TCF4 deficiency promotes cisplatin-induced ferroptosis in vitro and in vivo. Thus, we demonstrate that the aberrant activation of the Wnt/beta-catenin signaling confers ferroptosis resistance and suggests a potential therapeutic strategy to enhance chemo-sensitivity for advanced GC patients.

Xu (2021) YKT6, as a potential predictor of prognosis and immunotherapy response for oral squamous cell carcinoma, is related to cell invasion,

BackgroundOral squamous cell carcinoma (OSCC) is one of the most common malignant tumors worldwide. Patients with poorly differentiated OSCC often exhibit a poor prognosis. AUNIP (Aurora Kinase A and Ninein Interacting Protein), also known as AIBp, plays a key role in cell cycle and DNA damage repair. However, the function of AUNIP in OSCC remains elusive.MethodsThe differentially expressed genes (DEGs) were obtained using R language. Receiver operating characteristic curve analysis was performed to identify diagnostic markers for OSCC. The effectiveness of AUNIP in diagnosing OSCC was evaluated by machine learning. AUNIP expression was analyzed in publicly available databases and clinical specimens. Bioinformatics analysis and in vitro experiments were conducted to explore biological functions and prognostic value of AUNIP in OSCC.FindingsThe gene integration analysis revealed 90 upregulated DEGs. One candidate biomarker, AUNIP, for the diagnosis of OSCC was detected, and its expression gradually increased along with malignant differentiation of OSCC. Bioinformatics analysis demonstrated that AUNIP could be associated with tumor microenvironment, human papillomavirus infection, and cell cycle in OSCC. The suppression of AUNIP inhibited OSCC cell proliferation and resulted in G0/G1 phase arrest in OSCC cells. The survival analysis showed that AUNIP overexpression predicted poor prognosis of OSCC patients.Interpretation: AUNIP could serve as a candidate diagnostic and prognostic biomarker for OSCC and suppression of AUNIP may be a potential approach to preventing and treating OSCC.FundTaishan Scholars Project in Shandong Province (ts201511106) and the National Natural Science Foundation of China (Nos. 61603218).

BackgroundHistones chaperones have been found to play critical roles in tumor development and progression. However, the role of histone chaperone CHAF1A in gastric carcinogenesis and its underlying mechanisms remain elusive.MethodsCHAF1A expression in gastric cancer (GC) was analyzed in GEO datasets and clinical specimens. CHAF1A knockdown and overexpression were used to explore its functions in gastric cancer cells. The regulation and potential molecular mechanism of CHAF1A expression in gastric cancer cells were studied by using cell and molecular biological methods.FindingsCHAF1A was upregulated in GC tissues and its high expression predicted poor prognosis in GC patients. Overexpression of CHAF1A promoted gastric cancer cell proliferation both in vitro and in vivo, whereas CHAF1A suppression exhibited the opposite effects. Mechanistically, CHAF1A acted as a co-activator in the Wnt pathway. CHAF1A directly interacted with TCF4 to enhance the expression of c-MYC and CCND1 through binding to their promoter regions. In addition, the overexpression of CHAF1A was modulated by specificity protein 1 (Sp1) in GC. Sp1 transcriptionally enhanced the expression of CHAF1A in GC. Furthermore, CHAF1A expression induced by Helicobacter pylori was Sp1 dependent.InterpretationCHAF1A is a potential oncogene in GC, and may serve as a novel therapeutic target for GC treatment.

Gastric cancer (GC) is one of the most common and malignant pathologies, and a significant portion of GC incidences develops from Helicobacter pylori (Hp) ‐induced chronic gastritis. Although the exact mechanisms of GC are complex and poorly understood, gastric carcinogenesis is a good model to investigate how inflammation and infection collaboratively promote tumorigenesis. Yes‐associated protein 1 (YAP1) is the key effector of the Hippo pathway, which is silenced in most human cancers. Herein, we verified the tumor‐promoting effect of YAP1 in vitro, in vivo, and in human specimens. We revealed that YAP1 displays nuclear translocation and works with TEAD to activate transcription of the crucial inflammatory cytokine IL‐1β in gastric cells infected with Hp . As IL‐1ß accounts for inflammation‐associated tumorigenesis, this process can lead to gastric carcinogenesis. Thus, in addition to activating proliferation genes, YAP1 also plays a major role in inflammation amplification by activating inflammatory cytokine genes. Excitingly, our research demonstrates that transfection of mutant plasmid YAP‐5SA/S94A or addition of the drug verteporfin, both of which are thought to disrupt the YAP1‐TEAD interaction, can arrest the carcinogenesis process. These findings can provide new approaches to GC treatment.

BackgroundRhythm abnormalities are crucial for diverse diseases. However, their role in disease progression induced by Helicobacter pylori (H. pylori) remains elusive.MethodsH. pylori infection was used in in vivo and in vitro experiments to examine its effect on rhythmic genes. The GEO database was used to screen H. pylori affecting rhythm genes, and the effect of rhythm genes on inflammatory factors. Chromatin immunoprecipitation and dual luciferase assays were used to further find out the regulation between molecules. Animal models were used to confirm the relationship between rhythm genes and H. pylori-induced inflammation.FindingsBMAL1 disorders aggravate inflammation induced by H. pylori. Specifically, H. pylori induce BMAL1 expression in vitro and in vivo through transcriptional activation of LIN28A, breaking the circadian rhythm. Mechanistically, LIN28A binds to the promoter region of BMAL1 and directly activates its transcription under H. pylori infection. BMAL1 in turn functions as a transcription factor and enhances the expression of proinflammatory cytokine TNF-α, thereby promoting inflammation. Of note, BMAL1 dysfunction in the rhythm disorder animal model aggravates inflammatory response induced by H. pylori infection in vivo.InterpretationThese findings in this study imply the pathogenic relationship between BMAL1 and H. pylori. BMAL1 may serve as a potential diagnostic marker and therapeutic target for the early diagnosis and treatment of diseases related to H. pylori infection.FundNational Natural Science Foundation of China.