FXR controls duodenogastric reflux-induced gastric inflammation through negatively regulating ER stress-associated TNXIP/NLPR3 inflammasome.

Duodenogastric reflux (DGR) is closely associated with gastric inflammation and tumorigenesis; however, the precise mechanism is unclear. Hence, we aim to clarify this molecular mechanism and design an effective therapeutic strategy based on it. The present study found that DGR induced TXNIP/NLRP3 inflammasome activation and triggered pyroptosis in gastric mucosa in vitro and in vivo, in which endoplasmic reticulum (ER) stress via PERK/eIF2α/CHOP signaling was involved. Mechanistically, farnesoid X receptor (FXR) antagonized the DGR-induced PERK/eIF2α/CHOP pathway and reduced TXNIP and NLRP3 expression. Moreover, FXR suppressed NLRP3 inflammasome activation by physically interacting with NLRP3 and caspase-1. Administration of the FXR agonist OCA protected the gastric mucosa from DGR-induced barrier disruption and mucosal inflammation. In conclusion, our study demonstrates the involvement of TXNIP/NLRP3 inflammasome-mediated pyroptosis in DGR-induced gastric inflammation. FXR antagonizes gastric barrier disruption and mucosal inflammation induced by DGR. Restoration of FXR activity may be a therapeutic strategy for DGR-associated gastric tumorigenesis.

USP50 regulates NLRP3 inflammasome activation in duodenogastric reflux-induced gastric tumorigenesis.

Duodenogastric reflux (DGR) has been linked to the onset of gastric cancer (GC), although the precise mechanism is yet obscure. Herein, we aimed to investigate how refluxed bile acids (BAs) and macrophages are involved in gastric carcinogenesis. In both active human bile reflux gastritis and the murine DGR model, ubiquitin specific protease 50 (USP50) was dramatically raised, and macrophages were the principal leukocyte subset that upregulated USP50 expression. Enhancing USP50 expression amplified bile acid-induced NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and subsequent high-mobility group box protein 1 (HMGB1) release, while USP50 deficiency resulted in the reversed alteration. Mechanistically, USP50 interacted with and deubiquitinated apoptosis-associated speck-like protein containing CARD (ASC) to activate NLRP3 inflammasome. The release of HMGB1 contributes to gastric tumorigenesis by PI3K/AKT and MAPK/ERK pathways. These results may provide new insights into bile reflux-related gastric carcinogenesis and options for the prevention of DGR-associated GC.

Triphenyl phosphate exposure impairs colorectal health by altering host immunity and colorectal microbiota.

Colorectal diseases such as colorectal cancer (CRC) and inflammatory bowel disease (IBD) have become one of the most common public health concerns worldwide due to the increasing incidence. Environmental factors are one of the important causes of colorectal diseases, as they can affect the intestinal barrier function, immune response and microbiota, causing intestinal inflammation and tumorigenesis. Triphenyl phosphate (TPHP), a widely used organophosphorus flame retardant that can leach and accumulate in various environmental media and biota, can enter the human intestine through drinking water and food. However, the effects of TPHP on colorectal health have not been well understood. In this study, we investigated the adverse influence of TPHP exposure on colorectal cells (in vitro assay) and C57BL/6 mice (in vivo assay), and further explored the potential mechanism underlying the association between TPHP and colorectal disease. We found that TPHP exposure inhibited cell viability, increased apoptosis and caused G1/S cycle arrest of colorectal cells. Moreover, TPHP exposure damaged colorectal tissue structure, changed immune-related gene expression in the colorectal transcriptome, and disrupted the composition of colorectal microbiota. Importantly, we found that TPHP exposure upregulated chemokine CXCL10, which was involved in colorectal diseases. Our study revealed that exposure to TPHP had significant impacts on colorectal health, which may possibly stem from alterations in host immunity and the structure of the colorectal microbial community.

Risk factors for anastomotic leak and postoperative morbidity after right hemicolectomy for colon cancer: results from a prospective, multi-centre, snapshot study in China.

BACKGROUND: Right hemicolectomy is the standard treatment for right-sided colon cancer. There is variation in the technical aspects of performing right hemicolectomy as well as in short-term outcomes. It is therefore necessary to explore best clinical practice following right hemicolectomy in expert centres. METHODS: This snapshot study of right hemicolectomy for colon cancer in China was a prospective, multicentre cohort study in which 52 tertiary hospitals participated. Eligible patients with stage I-III right-sided colon cancer who underwent elective right hemicolectomy were consecutively enrolled in all centres over 10 months. The primary endpoint was the incidence of postoperative 30-day anastomotic leak. RESULTS: Of the 1854 patients, 89.9 per cent underwent laparoscopic surgery and 52.3 per cent underwent D3 lymph node dissection. The overall 30-day morbidity and mortality were 11.7 and 0.2 per cent, respectively. The 30-day anastomotic leak rate was 1.4 per cent. In multivariate analysis, ASA grade > II (P < 0.001), intraoperative blood loss > 50 ml (P = 0.044) and D3 lymph node dissection (P = 0.008) were identified as independent risk factors for postoperative morbidity. Extracorporeal side-to-side anastomosis (P = 0.031), intraoperative blood loss > 50 ml (P = 0.004) and neoadjuvant chemotherapy (P = 0.004) were identified as independent risk factors for anastomotic leak. CONCLUSION: In high-volume expert centres in China, laparoscopic resection with D3 lymph node dissection was performed in most patients with right-sided colon cancer, and overall postoperative morbidity and mortality was low. Further studies are needed to explore the optimal technique for right hemicolectomy in order to improve outcomes further.

Therapeutic effect of hydrogen and its mechanisms in kidney disease treatment.

Hydrogen is a simple, colorless, and biologically active small molecule gas that can react with reactive oxygen species. Recent research suggests that hydrogen possesses several biological effects, including antioxidant, anti-inflammatory, and anti-apoptotic effects, while exhibiting an extremely high level of safety. Hydrogen application has shown promise in treating a range of acute and chronic diseases, both benign and malignant. Importantly, an increasing number of clinical studies on hydrogen have demonstrated its efficacy and safety in treating various diseases. This review highlights the beneficial effects of hydrogen in kidney diseases, summarizes potential mechanisms by which hydrogen may act in these diseases, and proposes several promising avenues for future research.

USP51 facilitates colorectal cancer stemness and chemoresistance by forming a positive feed-forward loop with HIF1A.

In the current study, we have shown that USP51 promotes colorectal cancer stemness and chemoresistance, and high expression of USP51 predicts survival disadvantage in colorectal cancer patients. Mechanically, USP51 directly binds to Elongin C (ELOC) and forms a larger functional complex with VHL E3 ligase (USP51/VHL/CUL2/ELOB/ELOC/RBX1) to regulate the ubiquitin-dependent proteasomal degradation of HIF1A. USP51 efficiently deubiquitinates HIF1A and activates hypoxia-induced gene transcription. Conversely, the activation of HIF1A under hypoxia transcriptionally upregulates the expression of USP51. Thus, USP51 and HIF1A form a positive feedback loop. Further, we found that the SUMOylation of ELOC at K32 inhibits its binding to USP51. SUMO-specific protease 1 (SENP1) mediates the deSUMOylation of ELOC, promoting the binding of USP51 to ELOC and facilitating the deubiquitination and stabilization of HIF1A by USP51. Importantly, USP51 plays a crucial role in promoting the HIF1A and SENP1-dependent proliferation, migration, stemness, and chemoresistance under hypoxia in colorectal cancer. Together, our data revealed that USP51 is an oncogene stabilizing the pro-survival protein HIF1A, offering a potential therapeutic target for colorectal cancer.

SBP1 promotes tumorigenesis of thyroid cancer through TXN/NIS pathway.

BACKGROUND: As the tissue with the highest selenium content in the body, the occurrence and development of thyroid cancer are closely related to selenium and selenoproteins. Selenium-binding protein 1 (SBP1) has been repeatedly implicated in several cancers, but its role and molecular mechanisms in thyroid cancer remains largely undefined. METHODS: The expression of SBP1, sodium/iodide symporter (NIS) and thioredoxin (TXN) were analyzed in clinical samples and cell lines. Cell counting kit-8 (CCK-8) and tube formation assays were used to analyze the cell viability and tube formation of cells. Immunofluorescence was used to determine the expression of the NIS. Co-immunoprecipitation (Co-IP) assay was carried out to verify the interaction of SBP1 with TXN. The mouse xenograft experiment was performed to investigate the growth of thyroid cancer cells with SBP1 knockdown in vivo. RESULTS: SBP1 was significantly increased in human thyroid cancer tissues and cells, especially in anaplastic thyroid cancer. Overexpression of SBP1 promoted FTC-133 cell proliferation, and the culture supernatant of SBP1-overexpression FTC-133 cells promoted tube formation of human retinal microvascular endothelial cells. Knockdown of SBP1, however, inhibited cell proliferation and tube formation. Furthermore, overexpression of SBP1 inhibited cellular differentiation of differentiated thyroid cancer cell line FTC-133, as indicated by decreased expression of thyroid stimulating hormone receptors, thyroglobulin and NIS. Knockdown of SBP1, however, promoted differentiation of BHT101 cells, an anaplastic thyroid cancer cell line. Notably, TXN, a negative regulator of NIS, was found to be significantly upregulated in human thyroid cancer tissues, and it was positively regulated by SBP1. Co-IP assay implied a direct interaction of SBP1 with TXN. Additionally, TXN overexpression reversed the effect of SBP1 knockdown on BHT101 cell viability, tube formation and cell differentiation. An in vivo study found that knockdown of SBP1 promoted the expression of thyroid stimulating hormone receptors, thyroglobulin and NIS, as well as inhibited the growth and progression of thyroid cancer tumors. CONCLUSION: SBP1 promoted tumorigenesis and dedifferentiation of thyroid cancer through positively regulating TXN.

3-Bromopyruvate overcomes cetuximab resistance in human colorectal cancer cells by inducing autophagy-dependent ferroptosis.

Colorectal cancer (CRC) remains a leading cause of cancer-related death worldwide. Cetuximab, in combination with chemotherapy, is effective for treating patients with wild-type KRAS/BRAF metastatic CRC (mCRC). However, intrinsic or acquired drug resistance often limits the use of cetuximab. In this study, we investigated the potential of co-treatment with 3-Bromopyruvate (3-BP) and cetuximab to overcome cetuximab resistance in CRC, both in vitro and in vivo. Our results demonstrated that the co-treatment of 3-BP and cetuximab synergistically induced an antiproliferative effect in both CRC cell lines with intrinsic cetuximab resistance (DLD-1 (KRASG13D/-) and HT29 (BRAFV600E)) and in a cetuximab-resistant cell line derived from Caco-2 with acquired resistance (Caco-2-CR). Further analysis revealed that co-treatment induced ferroptosis, autophagy, and apoptosis. Mechanistically, co-treatment inhibited FOXO3a phosphorylation and degradation and activated the FOXO3a/AMPKα/pBeclin1 and FOXO3a/PUMA pathways, leading to the promotion of ferroptosis, autophagy, and apoptosis in DLD-1 (KRASG13D/-), HT29 (BRAFV600E), and Caco-2-CR cells. In conclusion, our findings suggest that co-treatment with 3-BP and cetuximab could be a promising strategy to overcome cetuximab resistance in human CRC.

A bionic "Trojan horse"-like gene delivery system hybridized with tumor and macrophage cell membrane for cancer therapy.

MiRNA-based gene therapy as a novel targeted therapy has yielded promising results in experimental cancer treatment, however, the inefficient delivery of miRNA to target tissues has limited its application in vivo. Here a unique dual-membrane-camouflaged miRNA21 antagomir delivery nanoplatform (M@NPs/miR21) with immune escape and homologous targeting properties was constructed by cancer cell membrane and macrophage membrane. Different from the single-cell membrane camouflage strategy, the dual-membrane camouflage miRNA21 antagomir delivery nanoplatform based on modification of CD47 protein with immune escape signal and galectin-3 protein with tumor cell aggregation enables efficient, safe and targeted therapy for colon cancer and lung metastases. Camouflaged with the dual-cell membrane, the "Trojan horse" like "pseudo-tumor cell" and/or "pseudo-macrophage" (M@NPs/miR21) carried the target gene miR21 antagomir to the tumor site and showed significant anti-tumor properties at the periphery and the core of subcutaneous tumor tissues. In addition, M@NPs/miR21 was more likely to penetrate dense tumor tissues and function within the tumor mass than NPs/miR21 without membrane coating. M@NPs/miR21 can deliver miR21 antagomir into MC38 cancer cells and tumor tissues, promote tumor apoptosis, and regulate the expression of Bcl2 and Ki67. Moreover, the M@NPs/miR21 gene delivery system not only can effectively inhibit the progression of subcutaneous tumors and lung metastases, but also showed minimal toxicity and good biosafety, making this delivery system particularly attractive for future translational research.

The Single Nucleotide Polymorphisms rs4143370 and rs34904192 in MIR155HG Were Associated with Esophageal Cancer Risk in the Chinese Han Population.

INTRODUCTION: MIR155HG has been found to play an important role in malignant tumors, but little research has been done on its association with esophageal cancer (ESCC). The aim of this study was to investigate the relationship between MIR155HG polymorphisms and ESCC susceptibility in the Chinese Han population. METHODS: 511 ESCC patients and 487 healthy controls were selected for this study. All subjects were genotyped using the Agena MassARRAY platform. We assessed the association between seven single nucleotide polymorphisms (SNPs) of the MIR155HG and ESCC risk by genetic model analysis. The false discovery rate (FDR) test and Bonferroni correction were usually used to detect false positives for the results. Meanwhile, the interaction between SNPs was analyzed by multifactor dimensionality reduction software to predict the ESCC risk. RESULTS: The C allele of rs4143370 and the A allele of rs34904192 in MIR155HG can increase the risk of ESCC (odds ratio (OR) = 1.33, p = 0.024; OR = 1.30, p = 0.013). Furthermore, rs4143370 and rs34904192 were associated with an increased risk of ESCC. Stratified analysis showed that MIR155HG SNPs (rs4143370 and rs34904192) significantly increased ESCC risk in males. MIR155HG SNPs (rs4143370, rs34904192, and rs928883) were also strongly associated with an increased risk of ESCC in people aged >64 years. In addition, haplotype analysis of the seven SNPs of the MIR155HG showed that the CC haplotype was associated with ESCC risk (OR = 1.34, p = 0.024). CONCLUSION: This study revealed that MIR155HG SNPs were associated with an increased risk of ESCC. The results provided clues for clarifying the role of MIR155HG in ESCC.

Evaluation of Fourier transform infrared (FTIR) spectroscopy with multivariate analysis as a novel diagnostic tool for lymph node metastasis in gastric cancer.

Fourier transform infrared (FTIR) spectroscopy is a vibration spectroscopy that uses infrared radiation to vibrate to absorb the molecular bonds in its absorbed sample. The main purpose of this study was to evaluate FTIR spectroscopy as a novel diagnostic tool for lymph node metastasis (LNM) of gastric cancer. We collected 160 fresh non-metastatic and metastatic lymph nodes (80 each) from 60 patients with gastric cancer for spectral analysis. FTIR spectra of lymph node (LN) samples were obtained in the wavenumber range of 4000 cm-1 to 900 cm-1. We calculated the changes in the ratio of spectral intensity (/ I1460). Principal component analysis (PCA) and Fisher's discriminant analysis (FDA) were used to distinguish malignant from normal LN. Four significant bands at 1080 cm-1, 1640 cm-1, 1740 cm-1 and 3260 cm-1 separated metastatic and non-metastatic LN spectra into two distinct groups by PCA.T-tests showed that, along with the relative intensity ratios (I1080/I1460, I1640/I1460, I3260/I1460, I1740/I1460), these band ratios were also able to differentiate between malignant and benign LN spectra. Six parameters (P1080 cm-1, P1300 cm-1, I1080/I1460, I1640/I1460, I3260/I1460, I1740/I1460) were selected as independent factors to set up discriminant functions. The sensitivity of FTIR spectroscopy in diagnosing LNM was 95 % by discriminant analysis. Our study suggested that FTIR spectroscopy can be a useful tool to examine LNM with high sensitivity and specificity for LNM diagnosis. Therefore it can be used in clinical practice as a non-invasive method.

Sotetsuflavone ameliorates Crohn's disease-like colitis by inhibiting M1 macrophage-induced intestinal barrier damage via JNK and MAPK signalling.

OBJECTIVES: Intestinal inflammation and intestinal barrier dysfunction are two important pathological changes in Crohn's disease (CD). Sotetsuflavone (SF) is a natural monomeric herbal compound with anti-inflammatory and cytoprotective effects that is mostly nontoxic. The effect of SF on CD-like spontaneous colitis was investigated in this study. METHODS: Il-10-/- mice were used as a CD model and were administered different doses of SF. Lipopolysaccharide (LPS) plus IFN-γ-induced macrophages (RAW264.7) and a coculture system (RAW264.7 and organoids) were used in vitro. The protective effects of SF against CD-like colitis and macrophage differentiation and the mechanisms were evaluated. RESULTS: SF treatment markedly improved spontaneous colitis in the CD model, as shown by the following evidence: reductions in the DAI, macroscopic scores (3.63 ± 1.30), colonic tissue inflammatory scores (2 ± 0.76) and proinflammatory factor levels and the attenuation of colon shortening (8 ± 0.93 cm) and weight loss (1.75 ± 1.83 g). Decreased intestinal permeability and intestinal bacterial translocation rates provided evidence of the protective effect of SF on intestinal barrier function. We also found that SF suppressed M1 macrophage-induced inflammatory responses. In the coculture system of mouse colonic organoids and RAW264.7 cells, SF significantly ameliorated M1 macrophage-induced intestinal epithelial damage. In addition, SF inhibited JNK and MAPK (p38) signalling in both Il-10-/- mice and LPS plus IFN-γ-induced macrophages (RAW264.7). CONCLUSIONS: The protective effects of SF against CD-like colitis may be achieved partially by inhibiting M1 macrophage-induced intestinal barrier damage via JNK and p38 signalling. SF may have therapeutic potential for treating CD, especially considering its safety.

Naringin Inhibits the Proliferation, Migration, Invasion and Epithelial-to-Mesenchymal Transition of Gastric Cancer Cells via the PI3K/AKT Signaling Pathway.

Background: Gastric cancer is a common malignant tumor of the human digestive system. Currently, the treatment of gastric cancer is still dominated by radiotherapy, chemotherapy and surgery. Although the treatment is very effective, we are also trying to find new treatment methods. Traditional Chinese Medicine (TCM) may play an important role in the treatment of gastric cancer. Study Objective: The aim of this study is to explore the effects of naringin on the proliferation, migration, invasion and apoptosis of gastric cancer and its potential mechanisms. Methods: MGC803 and MKN45 viability were detected by MTT assay. The effects of naringin on cell cloning, migration and invasion were determined by colony formation assay, cell scratch test and transwell assay (ThermoFisher Scientific™, Waltham, Massachusetts USA), respectively. Cell cycle and apoptosis were assayed by flow cytometry. Associated proteins were measured using Western blot and immunohistochemistry (IHC). The experimental results were further verified in nude mice. Setting: This study was carried out in Department of Experimental Animal Center of Xi'an Jiaotong University and the Translation Medicine Center of the First Affiliated Hospital of Xi'an Jiaotong University in China. Results: Cells remained mainly in G0/G1 phase and apoptosis was increased. The nude mouse model showed that naringin treatment could inhibit the growth of tumors in nude mice. Cell scratch tests and transwell assay showed that the invasion and migration abilities of the gastric cancer cell line were significantly reduced after naringin treatment. Western blot showed that the expression of Vimentin, Zeb1 and P-AKT was downregulated and that E-cadherin was upregulated after naringin treatment. Conclusion: Naringin can block the cell-cycle, induce cancer cell apoptosis, and inhibit the epithelial mesenchymal transition (EMT) process by inhibiting the PI3K-AKT/Zeb1 pathway in gastric cancer cells. Therefore, naringin can inhibit the development of gastric cancer.

LINC00339 accelerates invasion and migration of colorectal cancer via mediating miRNA-30a-5p.

To analyze the biological function of LINC00339 in the progression of colorectal cancer (CRC). We aim to provide directions in the early-stage treatment of CRC. LINC00339 level in 60 paired CRC tissues and paracancerous tissues was examined by quantitative real-time polymerase chain reaction (qRT-PCR). The correlation between the LINC00339 level and clinical parameters was analyzed. Moreover, the LINC00339 level in CRC cell lines was determined as well. LINC00339 expression was changed in HCT-8 and HCT-116 cell lines by transfection of LINC00339 overexpression plasmid or anti-LINC00339. The regulatory effects of LINC00339 on the migratory and invasive abilities of CRC cells were evaluated through a series of functional experiments. Dual-luciferase reporter gene assay and rescue experiments were conducted to verify the interaction of LINC00339 and miRNA-30a-5p in mediating the progression of CRC. LINC00339 was upregulated in CRC tissues relative to paracancerous tissues. CRC patients with higher levels of LINC00339 had higher rates of lymph node metastasis and distant metastasis, and worse prognosis than those with lower levels. Knockdown of LINC00339 attenuated migratory and invasive abilities of HCT-116 cells. Overexpression of LINC00339 in HCT-8 obtained the opposite trends. In addition, we verified a negative correlation between LINC00339 and miRNA-30a-5p in CRC tissues. LINC00339 served as a ceRNA to absorb miRNA-30a-5p. Rescue experiments confirmed that miRNA-30a-5p knockdown revered the regulatory effects of LINC00339 on the migratory and invasive abilities of CRC cells. LINC00339 was closely correlated to metastasis and poor prognosis of CRC. It accelerates CRC cells to migrate and invade via mediating miRNA-30a-5p.

Development and validation of a new stage-specific nomogram model for predicting cancer-specific survival in patients in different stages of colon cancer: A SEER population-based study and external validation.

Background: The effects of laterality of the primary tumor on survival in patients in different stages of colon cancer are contradictory. We still lack a strictly evaluated and validated survival prediction tool, considering the different roles of tumor laterality in different stages. Methods: A total of 101,277 and 809 colon cancer cases were reviewed using the Surveillance, Epidemiology, and End Results database and the First Affiliated Hospital of Xi 'an Jiaotong University database, respectively. We established training sets, internal validation sets and external validation sets. We developed and evaluated stage-specific prediction models and unified prediction models to predict cancer-specific survival and compared the prediction abilities of these models. Results: Compared with right-sided colon cancers, the risk of cancer-specific death of left-sided colon cancer patients was significantly higher in stage I/II but was markedly lower in stage III patients. We established stage-specific prediction models for stage I/II and stage III separately and established a unified prediction model for all stages. By evaluating and validating the validation sets, we reported high prediction ability and generalizability of the models. Furthermore, the stage-specific prediction models had better predictive power and efficiency than the unified model. Conclusions: Right-sided colon cancer patients have better cancer-specific survival than left-sided colon cancer patients in stage I/II and worse cancer-specific survival in stage III. Using stage-specific prediction models can further improve the prediction of cancer-specific survival in colon cancer patients and guide clinical decisions.

A novel chromatin regulator signature predicts the prognosis, clinical features and immunotherapy of colon cancer.

Aim: To elucidate the potential function and prognostic value of chromatin regulators (CRs) in colon cancer. Materials & methods: A comprehensive analysis of CR RNA expression data from public databases was conducted. Results: The authors successfully established and validated a 17 CR-based signature using public databases. Ten CRs of the signature were eventually verified at the protein level using the Human Protein Atlas database. Functional enrichment showed that CRs were significantly enriched in cancer-related pathways. This signature was remarkably relevant to immune cell infiltration, immune checkpoints, tumor immune dysfunction and exclusion (TIDE) score and drug sensitivity. Conclusion: The authors identified a novel, reliable prognostic signature for colon cancer. The study provided new insights into the function of CRs and has important clinical implications for immunotherapy for colon cancer.

Intestinal Gasdermins for regulation of inflammation and tumorigenesis.

Gasdermins (GSDMs) protein family express in intestinal epithelial cells or lamina propria immune cells, and play a nonnegligible function during gut homeostasis. With the gradually in-depth investigation of GSDMs protein family, the proteases that cleave GSDMA-E have been identified. Intestinal GSDMs-induced pyroptosis is demonstrated to play a crucial role in the removal of self-danger molecules and clearance of pathogenic organism infection by mediating inflammatory reaction and collapsing the protective niche for pathogens. Simultaneously, excessive pyroptosis leading to the release of cellular contents including inflammatory mediators into the extracellular environment, enhancing the mucosal immune response. GSDMs-driver pyroptosis also participates in a novel inflammatory cell death, PANoptosis, which makes a significant sense to the initiation and progression of gut diseases. Moreover, GSDMs are expressed in healthy intestinal tissue without obvious pyroptosis and inflammation, indicating the potential intrinsic physiological functions of GSDMs that independent of pyroptotic cell death during maintenance of intestinal homeostasis. This review provides an overview of the latest advances in the physiological and pathological properties of GSDMs, including its mediated pyroptosis, related PANoptosis, and inherent functions independent of pyroptosis, with a focus on their roles involved in intestinal inflammation and tumorigenesis.

DFNA5 inhibits colorectal cancer proliferation by suppressing the mTORC1/2 signaling pathways via upregulation of DEPTOR.

The human deafness, autosomal dominant 5 gene (DFNA5), a newly discovered executor of pyroptosis, has been strongly implicated in the tumorigenesis of several human cancers. However, an understanding of the functional role of DFNA5 in the development and progression of colorectal cancer (CRC) is limited. In this study, we demonstrated that DFNA5 was downregulated in CRC tissues. Ectopic expression of DFNA5 inhibited tumor cell growth in vitro, retarded tumor formation in vivo, and blocked a cell-cycle transition from the G0/G1 to the S phase, whereas a DFNA5 knockdown promoted cell proliferation. Western blotting showed that the levels of cell cycle-related proteins, including cyclin D1, cyclin E, CDK2, and p21, were accordingly altered upon DFNA5 overexpression or DFNA5 knockdown. Mechanistic studies indicated that DFNA5 exerted its tumor suppressor functions by antagonizing mTORC1/2 signaling via upregulation of DEPTOR. In addition, blockage of mTORC1/2 signaling by Torin-1 abolished the accelerative proliferation by DFNA5 knockdown. In conclusion, these results indicated that DFNA5 inhibits the proliferation and tumor formation of colon cancer cells by suppressing mTORC1/2 signaling.