Mitochondrial-related genes PDK2, CHDH, and ALDH5A1 served as a diagnostic signature and correlated with immune cell infiltration in ulcerative colitis.

We conducted an investigation to determine the potential of mitochondrial-related genes as diagnostic biomarkers in ulcerative colitis (UC), while also examining their association with immune cell infiltration. To achieve this, we acquired four datasets pertaining to UC, which included gene expression arrays and clinical data, from the GEO database. Subsequently, we selected three signature genes (PDK2, CHDH, and ALDH5A1) to construct a diagnostic model for UC. The nomogram and ROC curves exhibited exceptional diagnostic efficacy. Following this, quantitative real-time polymerase chain reaction and western blotting assays validated the decreased mRNA and protein expression of PDK2, CHDH, and ALDH5A1 in the model of UC cells and dextran sulfate sodium salt (DSS)-induced mice colitis tissues, aligning with the findings in the risk model. This investigation suggested a negative correlation between the expression of ALDH5A1, CHDH, and PDK2 and the infiltration of M1 macrophages. Then, immunofluorescence analysis confirmed the augmented expression of CD86 in the tissue of mice subjected to DSS, while a diminished expression of ALDH5A1, CHDH, and PDK2 was observed. Consequently, it can be inferred that targeting mitochondria-associated genes, namely PDK2, CHDH, and ALDH5A1, holds potential as a viable strategy for prognostic prediction and the implementation of immune therapy for UC.

Receptor-interacting protein kinase 2 is associated with tumor immune infiltration, immunotherapy-related biomarkers, and affects gastric cancer cells growth in vivo.

Background: The objective of this study was to analyze the research trend of four RIPK genes (RIPK1, RIPK2, RIPK3, and RIPK4), their expression variations in tumors, and the correlation between RIPK2 expression and immune-related biomarkers in gastric cancer (GC). Methods: The PubMed database was utilized to investigate the research trend surrounding four RIPKs genes in tumors. The ULCAN database was employed to analyze the differential expression of these four RIPKs genes. TCGA data were utilized to examine the association between RIPK2 expression and various factors including tumor immune infiltration and immune-related biomarkers. Lastly, the impact of targeting RIPK2 on the growth of GC cells was confirmed through tumor formation assay, immunohistochemistry, and Tunnel assays. Results: In the field of tumor biology, there has been a sustained increase in research focused on the four RIPKs genes over the past decade. Four RIPKs genes are differentially expressed in a majority of tumors. Furthermore, this investigation has unveiled a connection between the expression of RIPK2 and the infiltration of four immune cells, as well as the presence of RNA methylation modifying enzymes, specifically m1A, m6A, and m5C, in GC. Additionally, RIPK2 expression was associated with the genes related to immune checkpoint regulation, as well as genes associated with immunoinhibitors and immunostimulators. It was also revealed that RIPK2 expression was correlated to immunotherapy response biomarkers, namely MSI and TMB, and tumor stemness. Ultimately, it was demonstrated that targeting the RIPK2 effectively regulated GC cells growth through the suppression of PCNA expression and the induction of apoptosis. Conclusion: The expression of RIPK2 is correlated with immune cell infiltration, RNA methyltransferase activity, tumor stemness, checkpoint-related genes, and immunotherapy-related biomarkers. Suppression of RIPK2 impedes the growth of GC cells in vivo. Consequently, RIPK2 holds promise as a viable immunotherapy target for various types of cancer.

SDR16C5 promotes proliferation and migration and inhibits apoptosis in pancreatic cancer.

Pancreatic cancer (PAAD) is usually found when it is already in its advanced stage, which has limited options available for treatment and poor overall survival. The SDR16C5 gene is necessary for embryonic and adult tissue differentiation, development, and apoptosis, and it also participates in immune response and regulates energy metabolism. However, the role of SDR16C5 in PAAD remains unclear. In this study, we find that SDR16C5 was highly expressed in multiple tumors including PAAD. Furthermore, higher expression of SDR16C5 was significantly associated with poorer survival. We also find that the knockdown of SDR16C5 can inhibit PAAD cell proliferation and promote cell apoptosis by repressing Bcl-2, cleaved caspase 3, and cleaved caspase 9 protein expression. Moreover, silencing SDR16C5 inhibits the migration of PANC-1 and SW1990 cells by interrupting epithelial-mesenchymal transition. KEGG pathway analysis and immunofluorescence staining indicate that SDR16C5 is associated with immunity and may also participate in the development of PAAD through the IL-17 signaling pathway. Collectively, our findings provide evidence that SDR16C5 is overexpressed in PAAD patients and promotes its proliferation, migration, invasion, and apoptosis-inhibition of PAAD cells. Thus, SDR16C5 may be a potential prognostic and therapeutic target.

Comprehensive analysis of ZNF family genes in prognosis, immunity, and treatment of esophageal cancer.

BACKGROUND: As a common malignant tumor, esophageal carcinoma (ESCA) has a low early diagnosis rate and poor prognosis. This study aimed to construct the prognostic features composed of ZNF family genes to effectively predict the prognosis of ESCA patients. METHODS: The mRNA expression matrix and clinical data were downloaded from TCGA and GEO database. Using univariate Cox analysis, lasso regression and multivariate Cox analysis, we screened six prognosis-related ZNF family genes to construct the prognostic model. We then used Kaplan-Meier plot, time-dependent receiver operating characteristic (ROC), multivariable Cox regression analysis of clinical information, and nomogram to evaluate the prognostic value within and across sets, separately and combined. We also validated the prognostic value of the six-gene signature using GSE53624 dataset. The different immune status was observed in the single sample Gene Set Enrichment Analysis (ssGSEA). Finally, real-time quantitative PCR was used to detect the expression of six prognostic ZNF genes in twelve pairs of ESCA and adjacent normal tissues. RESULTS: A six prognosis-related ZNF family genes model consisted of ZNF91, ZNF586, ZNF502, ZNF865, ZNF106 and ZNF225 was identified. Multivariable Cox regression analysis revealed that six prognosis-related ZNF family genes were independent prognostic factors for overall survival of ESCA patients in TCGA and GSE53624. Further, a prognostic nomogram including the riskScore, age, gender, T, stage was constructed, and TCGA/GSE53624-based calibration plots indicated its excellent predictive performance. Drug Sensitivity and ssGSEA analysis showed that the six genes model was closely related to immune cells infiltration and could be used as a potential predictor of chemotherapy sensitivity. CONCLUSION: We identified six prognosis-related ZNF family genes model of ESCA, which provide evidence for individualized prevention and treatment.

Fusobacterium nucleatum promotes esophageal squamous cell carcinoma progression and chemoresistance by enhancing the secretion of chemotherapy-induced senescence-associated secretory phenotype via activation of DNA damage response pathway.

Senescence frequently occurs in cancer cells in response to chemotherapy (called therapy-induced senescence). Senescent cells can exert paracrine effects through the senescence-associated secretory phenotype (SASP) promoting cancer recurrence and chemoresistance. The altered gut microbiota has been closely associated with cancer progression through the direct interaction with cancer cells. However, little is known about the relationship between the gut microbiota and therapy-induced senescent cells. This study aimed to explore the impact of the gut microbiota on therapy-induced senescent cells and the SASP. We found that esophageal squamous cell carcinoma (ESCC) cells were induced into senescence following platinum-based chemotherapy, accompanied by the secretion of a robust SASP. Furthermore, senescent ESCC cells exerted a tumor-promoting effect through the SASP both in vitro and in vivo. Through 16S rRNA gene sequencing and fluorescence in situ hybridization, we identified that Fusobacterium nucleatum (F. nucleatum) was abundant in human ESCC cancerous tissues and correlated with poor prognosis in ESCC patients. Notably, F. nucleatum further promoted the secretion of the SASP by senescent ESCC cells. Compared with the conditioned medium from senescent ESCC cells, the conditioned medium from F. nucleatum-treated senescent ESCC cells accelerated tumor growth in xenograft models, enhanced migration and invasion abilities, and potentiated chemoresistance both in vitro and in vivo. Mechanistically, F. nucleatum invaded and survived in senescent ESCC cells and induced an increase in DNA damage to further activate the DNA damage response pathway, thus enhancing the SASP. Altogether, these findings reveal for the first time that F. nucleatum promotes the secretion of chemotherapy-induced SASP to drive ESCC progression and chemoresistance, which supports F. nucleatum as a potential target for ESCC therapy.

Fusobacterium nucleatum promotes proliferation in oesophageal squamous cell carcinoma via AHR/CYP1A1 signalling.

Fusobacterium nucleatum (Fn) is reportedly involved in poor prognosis of oesophageal squamous cell carcinoma (ESCC), but the responsible mechanisms remain unclear. The present study aimed to explore the function of Fn in ESCC progression, and to identify the key genes or signals involved. Fluorescence in situ hybridization and quantitative PCR assays were applied to measure the abundance of Fn in ESCC tissues, finding that ESCC tissues displayed a higher abundance of Fn compared to adjacent tissues. Furthermore, Fn abundance in advanced ESCC tissues was found to be higher than that in early stage ESCC. The proliferation assays and wound healing assays indicated that Fn infection promoted ESCC cell proliferation and migration. Based on high-throughput sequencing, cytochrome P450 1A1 (CYP1A1) was the most significantly upregulated (eightfold increase) gene, and AKT signalling was activated in KYSE-450 cells treated with Fn. Knocking down CYP1A1 or inactivating AKT signalling with LY294002 downregulated p-AKTS473 , inhibited cell proliferation, and compromised the proliferation effect induced by Fn in both in vitro and in vivo experiments. Inactivating the aryl hydrocarbon receptor (AHR) by CH-223191 reversed CYP1A1 expression induced by Fn and inhibited the proliferation of ESCC cells. Taken together, our findings indicate that Fn may promote ESCC cell proliferation via AHR/CYP1A1/AKT signalling. Targeting Fn or AHR/CYP1A1 signalling could yield approaches relevant to the treatment of ESCC.

Cyclophilin D Regulates Oxidative Stress and Apoptosis via Mitochondrial Permeability Transition Pore in Acute Acalculous Cholecystitis.

OBJECTIVE: Acute acalculous cholecystitis (AAC) is characterized by acute onset, rapid progression, high mortality, and various complications. Cyclophilin D (CypD) regulates the mitochondrial permeability transition pore (MPTP) and is involved in the occurrence of ischemia-reperfusion injury and inflammation; however, the role of CypD in AAC remains unclear. METHODS: Guinea pigs of 300-350 g were randomly divided into three groups, namely the sham group, the common bile duct ligation-24h group (CBDL-24h group), and the CBDL-48h group. Western blot and qRT-PCR were applied to analyze the differential expression of CypD in each group, and transmission electron microscopy was employed to detect changes in mitochondrial structure. Inhibiting the activity of CypD by Cyclosporine A (CsA), we evaluated the difference of mitochondrial utilizing mitochondrial swelling, reactive oxygen species (ROS) detection and mitochondrial membrane potential. RESULTS: Compared with the sham group, the prolongation of obstruction aggravated gallbladder inflammation and upregulated CypD expression in the CBDL-24h and CBDL-48h groups. The degree of mitochondrial swelling was increased, and the opening of MPTP was prolonged in the CBDL-24h and 48h groups. Decreasing the expression of CypD could repress the opening of MPTP, prevent manipulation of the mitochondrial membrane potential, and ultimately diminish the levels of intracellular ROS and apoptosis. CONCLUSION: CypD plays a proinflammatory role in the development of AAC by regulating the opening of MPTP. Inhibiting the activity of CypD could reduce the levels of ROS and apoptosis, rescue the function of mitochondria and finally alleviate AAC. Therefore, CypD might serve as a potential therapeutic target for ACC.