Cytoglobin promotes sensitivity to ferroptosis by regulating p53-YAP1 axis in colon cancer cells.

Ferroptosis is an iron-dependent mode of non-apoptotic cell death characterized by accumulation of lipid reactive oxygen species (ROS). As a regulator of ROS, cytoglobin (CYGB) plays an important role in oxygen homeostasis and acts as a tumour suppressor. However, the mechanism by which CYGB regulates cell death is largely unknown. Here, we show that CYGB overexpression increased ROS accumulation and disrupted mitochondrial function as determined by the oxygen consumption rate and membrane potential. Importantly, ferroptotic features with accumulated lipid ROS and malondialdehyde were observed in CYGB-overexpressing colorectal cancer cells. Moreover, CYGB significantly increased the sensitivity of cancer cells to RSL3- and erastin-induced ferroptotic cell death. Mechanically, both YAP1 and p53 were significantly increased based on the RNA sequencing. The knock-down of YAP1 alleviated production of lipid ROS and sensitivity to ferroptosis in CYGB overexpressed cells. Furthermore, YAP1 was identified to be inhibited by p53 knock-down. Finally, high expression level of CYGB had the close correlation with key genes YAP1 and ACSL4 in ferroptosis pathway in colon cancer based on analysis from TCGA data. Collectively, our results demonstrated a novel tumour suppressor role of CYGB through p53-YAP1 axis in regulating ferroptosis and suggested a potential therapeutic approach for colon cancer.

A pan-cancer study of spalt-like transcription factors 1/2/3/4 as therapeutic targets.

Spalt-like transcription factors (SALLs) are evolutionarily conserved proteins that participate in embryonic development. Four members of the SALL family, SALL1, SALL2, SALL3, and SALL4, are involved in cellular apoptosis, angiogenesis, invasion, and metastasis of tumors. We used the TCGA pan-cancer data to conduct a comprehensive analysis of SALL genes. High heterogeneity in the expression of these genes was observed across various cancers, SALL1 and SALL2 were downregulated, whereas SALL4 was upregulated. Moreover, we verified that SALL4 was commonly associated with survival disadvantage, whereas others were linked to a better prognosis. In renal cancer, SALL1, SALL2, and SALL3 showed downregulation, suggesting that they acted as tumor suppressors. Furthermore, SALLs were associated with immune infiltrate subtypes, with a close association between different degrees of infiltration of stromal cells and immune cells. DNA and RNA analyses in different tumors suggested different degrees of negative or positive correlation with tumor stem cell-like features. Finally, we revealed that SALLs were related to cancer cell resistance. Our results highlight the necessity to further study each SALL gene as a separate entity in specific types of cancer. Although this article showed that SALLs could be promising targets for cancer therapy, it needs further studies to validate the findings.

The functional sites of miRNAs and lncRNAs in gastric carcinogenesis.

Gastric cancer is one of the most common malignant diseases and has one of the highest mortality rates worldwide. Its molecular mechanisms are poorly understood. Recently, the functions of non-coding RNAs (ncRNAs) in gastric cancer have attracted wide attention. Although the expression levels of various ncRNAs are different, they may work together in a network and contribute to gastric carcinogenesis by altering the expression of oncogenes or tumor suppressor genes. They affect the cell cycle, apoptosis, motility, invasion, and metastasis. Dysregulated microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), including miR-21, miR-106, H19, and ANRIL, directly or indirectly regulate carcinogenic factors or signaling pathways such as PTEN, CDK, caspase, E-cadherin, Akt, and P53. Greater recognition of the roles of miRNAs and lncRNAs in gastric carcinogenesis can provide new insight into the mechanisms of tumor development and identify targets for anticancer drug development.

HMGA2 promotes resistance against paclitaxel by targeting the p53 signaling pathway in colorectal cancer cells.

Colorectal cancer is one of the most common malignancies and ranks second in terms of cancer-related mortality worldwide due to its metastasis, drug resistance, and reoccurrence. High-mobility gene group A2 (HMGA2) is overexpressed in colorectal cancer, contributing to the aggressiveness of tumor malignance, and promotes drug resistance in many types of cancer. However, the underlying molecular mechanism of HMGA2 is yet to be elucidated. In this study, we showed that HMGA2 is overexpressed in colorectal cancer tissue, and knockdown of HMGA2 significantly inhibited colorectal cancer cell growth and migratory capability. HMGA2 regulates the cancer cell response to a widely used anti-cancer drug, paclitaxel (PTX). HMGA2 knockdown increased cell death, whereas HMGA2 overexpression decreased cell death after PTX treatment. Furthermore, lower reactive oxygen species (ROS) levels and mitochondrial potential were detected in HMGA2 overexpression cells after PTX treatment. However, HMGA2 knockdown produced the opposite effect. RNA sequencing showed a p53 signaling pathway-dependent regulation in HMGA2 knockdown cells. Combined with p53 inhibitors and HMGA2 knockdown, a synergetic effect of more cell death was observed in colorectal cancer cells after PTX treatment. Thus, we showed that HMGA2 can activate p53 signaling to regulate colorectal cancer cell death after PTX treatment. Altogether, our results reveal novel insights into the molecular mechanisms underlying HMGA2-mediated cancer cell resistance against PTX and highlight the potential of targeting HMGA2 and p53 signaling for the therapeutic investigation of colorectal cancer.

Endoscopic Screening for Missed Lesions of Synchronous Multiple Early Gastric Cancer during Endoscopic Submucosal Dissection.

Aims: To evaluate the value of endoscopic screening during endoscopic submucosal dissection (ESD) in the detection of synchronous multiple early gastric cancer (SMEGC) and the risk factors for missed diagnosis of SMEGC. Methods: We conducted gastric endoscopic screening during ESD operation in 271 patients with early gastric cancer (EGC) referred for ESD, and endoscopic follow-up within 1 year after the operation. The detection and characteristics of SMEGC were analyzed in three stages: before ESD, during ESD operation, and within 1 year after ESD. Results: SMEGC was detected in 37 of 271 patients (13.6%). Among them, 21 patients with SMEGC (56.8%) were diagnosed before ESD, 9 (24.3%) were diagnosed with SMEGC by endoscopic screening during ESD operation, and 7 (18.9%) were found to have EGC lesions in the stomach during postoperative endoscopic follow-up within 1 year. The preoperative missed detection rate of SMEGC was 43.2%, and the rate of missed detection could be reduced by 24.3% (9/37) with endoscopic screening during ESD operation. Missed SMEGC lesions were more common in flat or depressed type and smaller in size than the lesions found before ESD. The presence of severe atrophic gastritis and age ≥60 years were significantly correlated with SMEGC (P < 0.05), while multivariate analysis showed that age ≥60 years was an independent risk factor (OR = 2.63, P < 0.05) for SMEGC. Conclusions: SMEGC lesions are apt to be missed endoscopically. Special attention should be paid to small, depressed, or flat lesions in detecting SMEGC, especially in elderly patients or (and) patients with severe atrophic gastritis. Endoscopic screening during ESD operation can effectively reduce the missed diagnosis rate of SMEGC.

Zenker's diverticulum treated with submucosal tunneling endoscopic septum division surgery: Two case reports.

INTRODUCTION: Zenker's diverticulum (ZD) refers to a pouch-like structure similar to the esophageal lumen formed from the herniation of the esophageal mucosa; this structure makes it difficult for food to pass through the esophagus to the stomach. The development of endoscopic technology has made minimally invasive surgical treatments for ZD possible. PATIENT CONCERNS: A female 72-year-old patient was admitted to our hospital due to recurrent dysphagia for more than 5 years. A 62-year-old female patient underwent a gastroscopic examination due to recurrent dysphagia for 10 years and aggravated dysphagia accompanied by bad breath for 1 year. DIAGNOSIS: A significant diverticulum with food residue at the entrance of the esophagus was found on gastroscopy in both cases. INTERVENTIONS: After completing a relevant examination and excluding surgical contraindications, both patients underwent submucosal tunneling endoscopic septum division. OUTCOMES: Both patients were discharged after symptoms alleviated on postoperative day 4. A 3-month follow-up gastroscopy showed the disappearance of the diverticulum and recovery of the esophageal anatomical structure. No symptom relapse was found at the 6-month follow-up assessment. CONCLUSION: Submucosal tunneling endoscopic septum division has become the most common minimally invasive treatment option. It is efficient and safe for relieving symptomatic ZD in the short term.

Carbonic anhydrase IV inhibits cell proliferation in gastric cancer by regulating the cell cycle.

Carbonic anhydrase IV (CA4) is silenced in colorectal cancer. However, the effect of CA4 on the development of gastric cancer (GC) is poorly understood. The present study aimed to determine the role of CA4 in GC tumorigenesis and its underlying molecular mechanism. The levels of CA4 in GC cells and tissues were evaluated by reverse transcription-quantitative PCR and immunohistochemistry. CA4 expression was suppressed in GC cells and tissues compared with adjacent healthy tissues and normal human gastric epithelial cells, respectively. This reduced expression was significantly associated with tumor size, invasion and differentiation. Analyses with a real-time cell analyzer and clonogenic assays were conducted to validate the impact of CA4 on GC cell lines (AGS and HGC-27) and normal human gastric epithelial cell line (GES-1) proliferation. The effects of CA4 on the cell cycle in GC cells were determined by flow cytometry. The levels of CA4 and cell cycle-associated proteins were confirmed by western blotting. CA4 overexpression inhibited GC cell proliferation and reduced colony-forming ability, arrested the cell cycle in the G2/M phase, inhibited cyclin B1 and cyclin-dependent kinase 2 expression and induced p21 expression. These results indicate that CA4 may serve an important role in GC tumorigenesis by inhibiting cellular proliferation via regulating the expression of cell cycle-associated proteins. CA4 may serve as a diagnostic biomarker and a potential therapeutic target in GC.

Meta-analysis of fish consumption and risk of pancreatic cancer in 13 prospective studies with 1.8 million participants.

A previous meta-analysis suggested no association between fish consumption and risk of pancreatic cancer. As several prospective studies with a large number of pancreatic cancer cases have emerged after that meta-analysis, we updated the evidence and examined the relationship in greater depth. We performed a literature search on PubMed and EMBASE databases through March 30, 2019 to identify potentially eligible studies. We used a random-effects model to compute summary relative risk (RR) with corresponding 95% confidence interval (CI). A total of 13 prospective studies comprising 4994 pancreatic cancer cases and 1,794,601 participants were included in the final analyses. Results of the meta-analysis showed that fish consumption was not significantly associated with risk of pancreatic cancer (RR 50-g/day = 1.03, 95% CI: 0.95-1.12), which was confirmed when stratifying the analysis by various methodological and population characteristics. There was a suggestion of difference by adjustment for family history of pancreatic cancer (Pdifference = 0.05), with fish consumption being associated with higher risk of pancreatic cancer in studies without adjustment for participants' family history (RR50-g/day = 1.09, 95% CI: 1.02-1.18), and a non-significant inverse association among studies with the adjustment (RR50-g/day = 0.93, 95% CI: 0.82-1.05). Results of this updated meta-analysis suggest that fish consumption is unlikely to be substantially associated with risk of pancreatic cancer.

Hypermethylated WNT10A and its clinical significance in colorectal cancer.

Colorectal cancer (CRC) is a heterogeneous disease in which unique subtypes are characterized by distinct genetic and epigenetic alterations. DNA methylation, a well-documented epigenetic modification, is a promising biomarker for the diagnosis and prognosis of cancers, including CRC. WNT10A is a member of the Wnt family. It belongs to the Wnt signaling pathway and is involved in CRC. However, studies regarding the methylation and expression of WNT10A in CRC are limited. In the current study, we analyzed the methylation status of WNT10A in 146 patients with CRC and normal controls. These samples were classified into two groups. The first group was an initial discovery set (i.e., fresh tissue samples from 40 patients with CRC and adjacent normal control samples). The second group was an independent validation set (i.e., formalin-fixed and paraffin-embeded [FFPE] samples from 106 patients with CRC and cutting edge tissues). The results showed a higher level of WNT10A hypermethylation of in CRC samples than in controls (Fresh tissue cohort: P = 2.8E-5; FFPE cohort: P = 3.6E-4).This finding was verified by WNT10A methylation data from The Cancer Genome Atlas portal (TCGA) (P = 1.9E-83). Subgroup analysis of clinical characteristics showed a higher WNT10A methylation level in elder patients (aged > 60 y) (P = 0.037) and, patients with distant metastasis (P = 0.033), rectal cancer (P = 0.03), and mucinous adenocarcinoma (P = 0.02). Furthermore, TCGA RNAseq data demonstrated lower WNT10A expression in patients with CRC than in controls (P = 4.0E-3) and showed a negative correlation between expression and methylation (r = -0.37, P = 5.7E-13). Moreover, the efficiency of WNT10A methylation for CRC diagnosis was analyzed in both cohorts of the present study and the TCGA cohorts, which indicated the potential use of WNT10A methylation as a tool for diagnosis of CRC.

Early diagnostic potential of APC hypermethylation in esophageal cancer.

BACKGROUND: The hypermethylation of APC gene is observed in various cancers, including esophageal cancer (EC). However, the association between APC methylation and the initiation and progression of EC is poorly understood. PURPOSE AND METHODS: The current study systematically reviewed studies on abnormal methylation of APC in EC and quantitatively synthesized 18 studies by meta-analysis involving 1008 ECs, 570 Barrett's esophagus (BE), and 782 controls. RESULTS: Our results showed higher methylation of APC in EC (OR = 23.33, P < 0.001) and BE (OR = 9.34, P < 0.001) than in normal controls. Whereas APC methylation in EC was similar to that in BE (P = 0.052), it was not associated with tumor stage (P = 0.204). Additionally, APC methylation was not significantly associated with overall survival (OS) and relapse-free survival (RFS) in patients with EC. The performance of APC methylation for the detection of EC and BE achieved areas under the receiver operating characteristic curves of 0.94 and 0.88, respectively. CONCLUSION: Our results imply that APC methylation detection is a potential diagnostic biomarker for EC and BE.