eIf3a mediates malignant biological behaviors in colorectal cancer through the PI3K/AKT signaling pathway.

Colorectal cancer (CRC) is among the most common gastrointestinal malignancies worldwide. eIF3a is highly expressed in a variety of cancer types, yet its role in CRC remains unclear. We introduced ectopic eIF3a expression in CRC cells to investigate its relevance to various malignant behaviors. Further, we silenced eIF3a to explore its effect on tumor growth in a nude mouse tumor xenograft model. Finally, the molecular mechanisms through which eIF3a regulates malignancy in CRC cells were explored through bioinformatics analysis combined with the use of a specific PI3K inhibitor (LY294002). eIF3a was highly expressed in the peripheral blood and cancer tissue of CRC patients. Malignancy and tumor growth were significantly inhibited by silencing eIF3a, while overexpression promoted malignant behaviors, with a positive correlation between PI3K/AKT activation and eIF3a expression. Taken together, eIF3a plays an oncogenic role in CRC by regulating PI3K/AKT signaling and is a potential biomarker for CRC diagnosis and prognostic monitoring.

SLC40A1 in iron metabolism, ferroptosis, and disease: A review.

Solute carrier family 40 member 1 (SLC40A1) plays an essential role in transporting iron from intracellular to extracellular environments. When SLC40A1 expression is abnormal, cellular iron metabolism becomes dysregulated, resulting in an overload of intracellular iron, which induces cell ferroptosis. Numerous studies have confirmed that ferroptosis is closely associated with the development of many diseases. Here, we review recent findings on SLC40A1 in ferroptosis and its association with various diseases, intending to explore new directions for research on disease pathogenesis and new therapeutic targets for prevention and treatment. This article is categorized under: Cancer > Genetics/Genomics/Epigenetics Metabolic Diseases > Molecular and Cellular Physiology.

Linc-ROR inhibits NK cell-killing activity by promoting RXRA ubiquitination and reducing MICB expression in gastric cancer patients.

Linc-ROR plays an important role in gastric cancer (GC) development and progression. This study sought to determine how the aberrant expression of Linc-ROR impacts GC progression and immune evasion, and to identify new targets for GC therapy. GC cells overexpressing Linc-ROR and GSAGS cells were cocultured with NK-92 cells, respectively, and Linc-ROR expression was determined using reverse transcription polymerase chain reaction. Linc-ROR overexpression experiments were used to measure the expression of MICB, a tumor protein that is recognized by natural killer (NK) cells. Bioinformatics analysis identified retinoid X receptor α (RXRA) and YY1 as MICB-specific transcription factors. Cotransfection and ubiquitinated drug experiments found that Linc-ROR promoted the ubiquitination and degradation of RXRA. Linc-ROR was upregulated in GC tissue and high expression was associated with tumor escape from NK-92 cell-mediated immunity. Linc-ROR overexpression inhibited the expression of MICB on the cell surface by degrading RXRA. These findings indicate that Linc-ROR promotes the binding of RXRA and E3 ligase UBE4B, reducing RXRA and MICB expression, and limiting NK cell-killing activity. Linc-ROR is a critical long noncoding RNA with a tumor-promoting function in GC and thus may serve as a potential therapeutic target.

Influence of tumor mycobiome on cancer pathogenesis (Review).

Cancer tissues harbor a large microbiome. There is growing evidence that the tumor microbiome is significantly correlated with the prognosis of cancer patients, but the exact underlying mechanisms have remained elusive. Although the tumor mycobiome is less abundant than the biome of bacteria, it is prevalent in most cancers in humans. The present review describes in detail the impact of the tumor mycobiome on cancer pathogenesis. The tumor mycobiome promotes tumor progression and metastasis by affecting the human immune system, maintaining a pro-inflammatory environment, producing aflatoxins, attenuating cell adhesion mechanisms and fungal-bacterial interactions. Furthermore, the tumor mycobiome likewise has great potential for cancer prevention, diagnosis and treatment.

Experience of management of pediatric upper gastrointestinal perforations: a series of 30 cases.

Background: This study aimed to explore the characteristics of pediatric upper gastrointestinal (UGI) perforations, focusing on their diagnosis and management. Methods: Between January 2013 and December 2021, 30 children with confirmed UGI perforations were enrolled, and their clinical data were analyzed. Two groups were compared according to management options, including open surgical repair (OSR) and laparoscopic/gastroscopic repair (LR). Results: A total of 30 patients with a median age of 36.0 months (1 day-17 years) were included in the study. There were 19 and 11 patients in the LR and OSR groups, respectively. In the LR group, two patients were treated via exploratory laparoscopy and OSR, and the other patients were managed via gastroscopic repair. Ten and three patients presented the duration from symptom onset to diagnosis within 24 h (p = 0.177) and the number of patients with hemodynamically unstable perforations was 4 and 3 in the LR and OSR groups, respectively. Simple suture or clip closure was performed in 27 patients, and laparoscopically pedicled omental patch repair was performed in two patients. There was no significant difference in operative time and length of hospital stay between the LR and OSR groups. Treatment failed in two patients because of severe sepsis and multiple organ dysfunction syndrome, including one with fungal peritonitis. Conclusion: Surgery for pediatric UGI perforations should be selected according to the general status of the patient, age of the patient, duration from symptom onset, inflammation, and perforation site and size. Antibiotic administration and surgical closure remain the main strategies for pediatric UGI perforations.

Dysregulation of Long Non-coding RNAs and mRNAs in Plasma of Clear Cell Renal Cell Carcinoma Patients Using Microarray and Bioinformatic Analysis.

Objective: The roles of long non-coding RNAs (lncRNAs) in the diagnosis of clear cell renal cell carcinoma (ccRCC) are still not well-defined. We aimed to identify differentially expressed lncRNAs and mRNAs in plasma of ccRCC patients and health controls systematically. Methods: Expression profile of plasma lncRNAs and mRNAs in ccRCC patients and healthy controls was analyzed based on microarray assay. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway-based approaches were used to investigate biological function and signaling pathways mediated by the differentially expressed mRNAs. SOCS2-AS1 was selected for validation using Real-Time PCR. The differentially expressed lncRNAs and mRNAs were further compared with E-MTAB-1830 datasets using Venn and the NetworkAnalyst website. The GEPIA and ULCAN websites were utilized for the evaluation of the expression level of differentially expressed mRNA and their association with overall survival (OS). Results: A total of 3,664 differentially expressed lncRNAs were identified in the plasma of ccRCC patients, including 1,511 up-regulated and 2,153 down-regulated lncRNAs (fold change ≥2 and P < 0.05), respectively. There were 2,268 differentially expressed mRNAs, including 932 up-regulated mRNAs and 1,336 down-regulated mRNAs, respectively (fold change ≥2 and P < 0.05). Pathway analysis based on deregulated mRNAs was mainly involved in melanogenesis and Hippo signaling pathway (P < 0.05). In line with the lncRNA microarray findings, the SOCS2-AS1 was down-regulated in ccRCC plasma and tissues, as well as in cell lines. Compared with the E-MTAB-1830 gene expression profiles, we identified 18 lncRNAs and 87 mRNAs differently expressed in both plasma and neoplastic tissues of ccRCC. The expression of 10 mRNAs (EPB41L4B, CCND1, GGT1, CGNL1, CYSLTR1, PLAUR, UGT3A1, PROM2, MUC12, and PCK1) was correlated with the overall survival (OS) rate in ccRCC patients based on the GEPIA and ULCAN websites. Conclusions: We firstly reported differentially expressed lncRNAs in ccRCC patients and healthy controls systemically. Several differentially expressed lncRNAs and mRNAs were identified, which might serve as diagnostic or prognostic markers. The biological function of these lncRNAs and mRNAs should be further validated. Our study may contribute to the future treatment of ccRCC and provide novel insights into cancer biology.

Nuclear FOXP3 inhibits tumor growth and induced apoptosis in hepatocellular carcinoma by targeting c-Myc.

The status of FOXP3 and its isoforms in hepatocellular carcinoma (HCC) is unclear. We aimed to investigate the expression and function of FOXP3 and its isoforms in HCC. The study was performed on 84 HCC patients, HCC cell lines and a mouse tumor model. The levels of FOXP3 and its isoforms were determined by nested PCR, quantitative real-time PCR and immunohistochemistry (IHC) staining. The correlation between their levels and clinicopathologic characteristics was analyzed. The full length of FOXP3 (FOXP3) and exon 3-deleted FOXP3 (FOXP3Δ3) were found to be the major isoforms in HCC. The levels of FOXP3Δ3 mRNA and protein in HCC tumor samples were not significantly different from their adjacent normal tissues. The high expression of FOXP3 protein in HCC patients showed a good overall survival. The overexpression of FOXP3 significantly reduced tumor cell proliferation, migration and invasion. The immunofluorescence result indicated that FOXP3 needed to be translocated into the nucleus to exert its inhibitory function. The luciferase assay demonstrated that FOXP3 could be synergistic with Smad2/3/4 to inhibit the oncogene c-Myc. The co-immunoprecipitation results further revealed that FOXP3 could interact with Smad2/3/4. The chromatin immunoprecipitation (ChIP) assay showed that both FOXP3 and Smad2/3/4 bound the promoter of the c-Myc to inhibit it. The in vivo mouse tumor model study confirmed the inhibitory effect of FOXP3. Collectively, the expression of tumor FOXP3 can inhibit the growth of HCC via suppressing c-Myc directly or indirectly via interacting with Smad2/3/4. Therefore, FOXP3 is a tumor suppressor in HCC.

Retraction of "UBE2C, Directly Targeted by miR-548e-5p, Increases the Cellular Growth and Invasive Abilities of Cancer Cells Interacting with the EMT Marker Protein Zinc Finger E-box Binding Homeobox 1/2 in NSCLC".

[This retracts the article DOI: 10.7150/thno.32738.].

Delayed bowel obstruction after seat belt injury: a case report.

BACKGROUND: Delayed bowel obstruction due to seat belt injury is extremely rare. The delayed onset of nonspecific symptoms makes a timely diagnosis difficult. A deep understanding of the characteristics of this condition is helpful for early diagnosis and treatment. CASE PRESENTATION: A 39-year-old male was transferred to our hospital from another hospital complaints of progressive abdominal distension and severe weakness. In the previous hospital, he was diagnosed with "adult megacolon" and was recommended for surgical treatment. In our hospital, he was diagnosed with delayed bowel obstruction due to seat belt injury and underwent surgical intervention. Following laparoscopic adhesiolysis and resection of the narrow small intestine, his symptoms improved rapidly, and he was discharged. CONCLUSION: Delayed bowel obstruction due to seat belt injury may present clinical symptoms any time after the injury. Imaging examination, ileus tube and small colonoscopy may provide us with valuable cues for the diagnosis and treatment of delayed bowel obstruction, and laparoscopy may be an alternative approach in surgical intervention.

Correction to: m6A mRNA methylation initiated by METTL3 directly promotes YAP translation and increases YAP activity by regulating the MALAT1-miR-1914-3p-YAP axis to induce NSCLC drug resistance and metastasis.

An amendment to this paper has been published and can be accessed via the original article.

The role of microRNA in cisplatin resistance or sensitivity.

INTRODUCTION: Cisplatin is a chemotherapy drug that has been used to treat a number of cancers for decades, and is still one of the most commonly used anti-cancer agents. However, some patients do not respond to cisplatin while other patients who were originally sensitive to cisplatin eventually develop chemoresistance, leading to treatment failure or/and tumor recurrence. AREAS COVERED: Different mechanisms contribute to cisplatin resistance or sensitivity, involving multiple pathways or/and processes such as DNA repair, DNA damage response, drug transport, and apoptosis. Among the various mechanisms, it appears that microRNAs play an important role in determining the resistance or sensitivity. In this article, we analyzed and summarized recent findings in this area, with the aim that these data can aid further research and understanding, leading to the eventual reduction of cisplatin resistance. EXPERT COMMENTARY: microRNAs can positively or negatively regulate cisplatin resistance by acting on molecules or/and pathways related to apoptosis, autophagy, hypoxia, cancer stem cells, NF-κB, and Notch1. It appears that the modulation of relevant microRNAs can effectively re-sensitize cancer cells to cisplatin regimen in certain types of cancers including breast, colorectal, gastric, liver, lung, ovarian, prostate, testicular, and thyroid cancers.

Immune Response in H. pylori-Associated Gastritis and Gastric Cancer.

Helicobacter pylori (H. pylori) is the dominant member of the gastric microbiota and has infected more than half of the human population, of whom 5-15% develop gastric diseases ranging from gastritis and metaplasia to gastric cancer. These diseases always follow inflammation induced by cell surface and intracellular receptors and subsequent signaling, such as the NF-κB pathway and inflammasomes. Some types of immune cells are recruited to enforce an antibacterial response, which could be impeded by H. pylori virulence factors with or without a specific immune cell. Following decreased inflammation, neoplasm may appear with a little immune surveillance and may inhibit antitumor immunity. Therefore, the balance between H. pylori-associated inflammation and anti-inflammation is crucial for human health and remains to be determined. Here, we discuss multiple inflammation and immunoregulatory cells in gastritis and summarize the main immune evasion strategies employed by gastric cancer.

Clinical Characteristics of COVID-19 Patients With Digestive Symptoms in Hubei, China: A Descriptive, Cross-Sectional, Multicenter Study.

OBJECTIVE: Since the outbreak of Coronavirus Disease 2019 (COVID-19) in December 2019, various digestive symptoms have been frequently reported in patients infected with the virus. In this study, we aimed to further investigate the prevalence and outcomes of COVID-19 patients with digestive symptoms. METHODS: In this descriptive, cross-sectional, multicenter study, we enrolled confirmed patients with COVID-19 who presented to 3 hospitals from January 18, 2020, to February 28, 2020. All patients were confirmed by real-time polymerase chain reaction and were analyzed for clinical characteristics, laboratory data, and treatment. Data were followed up until March 18, 2020. RESULTS: In the present study, 204 patients with COVID-19 and full laboratory, imaging, and historical data were analyzed. The average age was 52.9 years (SD ± 16), including 107 men and 97 women. Although most patients presented to the hospital with fever or respiratory symptoms, we found that 103 patients (50.5%) reported a digestive symptom, including lack of appetite (81 [78.6%] cases), diarrhea (35 [34%] cases), vomiting (4 [3.9%] cases), and abdominal pain (2 [1.9%] cases). If lack of appetite is excluded from the analysis (because it is less specific for the gastrointestinal tract), there were 38 total cases (18.6%) where patients presented with a gastrointestinal-specific symptom, including diarrhea, vomiting, or abdominal pain. Patients with digestive symptoms had a significantly longer time from onset to admission than patients without digestive symptoms (9.0 days vs 7.3 days). In 6 cases, there were digestive symptoms, but no respiratory symptoms. As the severity of the disease increased, digestive symptoms became more pronounced. Patients with digestive symptoms had higher mean liver enzyme levels, lower monocyte count, longer prothrombin time, and received more antimicrobial treatment than those without digestive symptoms. DISCUSSION: We found that digestive symptoms are common in patients with COVID-19. Moreover, these patients have a longer time from onset to admission, evidence of longer coagulation, and higher liver enzyme levels. Clinicians should recognize that digestive symptoms, such as diarrhea, are commonly among the presenting features of COVID-19 and that the index of suspicion may need to be raised earlier in at-risk patients presenting with digestive symptoms. However, further large sample studies are needed to confirm these findings.

Epithelial-mesenchymal transition may be involved in the immune evasion of circulating gastric tumor cells via downregulation of ULBP1.

BACKGROUND: Increasing numbers of studies have demonstrated that circulating tumor cells (CTCs) undergo a phenotypic change termed epithelial-mesenchymal transition (EMT), and researchers have proposed that EMT might provide CTCs with increased potential to survive in the different microenvironments encountered during metastasis through various ways, such as by increasing cell survival and early colonization. However, the exact role of EMT in CTCs remains unclear. METHODS: In this study, we identified CTCs of 41 patients with gastric cancer using Cyttel-CTC and im-FISH (immune-fluorescence in situ hybridization) methods, and tested the expression of EMT markers and ULBP1 (a major member of the NKG2D-natural killer [NK] group 2 member D-ligand family) on CTCs. Moreover, we investigated the relationship between the expression of EMT markers and ULBP1 on CTCs and gastric cancer cell lines. RESULTS: Our results showed that the CTCs of gastric cancer patients exhibited three EMT marker subtypes, and that the expression of ULBP1 was significantly lower on mesenchymal phenotypic CTCs (M+ CTCs) than on epithelial phenotypic CTCs (E+ CTCs). EMT induced by TGF-ß in vitro produced a similar phenomenon, and we therefore proposed that EMT might be involved in the immune evasion of CTCs from NK cells by altering the expression of ULBP1. CONCLUSIONS: Our study indicated that EMT might play a vital role in the immune invasion of CTCs by regulating the expression of ULBP1 on CTCs. These findings could provide potential strategies for targeting the immune evasion capacity of CTCs.

ZBP-89 negatively regulates self-renewal of liver cancer stem cells via suppression of Notch1 signaling pathway.

Liver cancer stem cells (LCSCs) initiate hepatocellular carcinoma (HCC) and contribute to its recurrence and treatment resistance. Studies have suggested ZBP-89 as a candidate tumor suppressor in HCC. We explored the role of ZBP-89 in the regulation of LCSCs. This study was performed in liver tissue samples from 104 HCC patients, 2 cell lines and mouse tumor models. We demonstrated that ZBP-89 was weakly expressed in LCSCs. Patients with high expression of LCSC markers displayed reduced survivals and higher recurrence rates after curative surgical operation. The expression of ZBP-89 was predictive for decreased recurrence. LCSC markers were negatively correlated with ZBP-89 in HCC tissues and in enriched liver tumor spheres. The exogenous expression of ZBP-89 attenuated the tumor-sphere formation and secondary colony formation capabilities of LCSCs in vitro and tumorigenicity in vivo. Furthermore, the negative effect of ZBP-89 on cancer stemness was Notch1-dependent. Localized with Notch1 intracellular domain (NICD1) in the nucleus, ZBP-89 repressed the Notch1 signaling pathway by competitive binding to NICD1 with MAML1. Collectively, ZBP-89 negatively regulates HCC stemness via inhibiting the Notch1 signaling.

m6A mRNA methylation initiated by METTL3 directly promotes YAP translation and increases YAP activity by regulating the MALAT1-miR-1914-3p-YAP axis to induce NSCLC drug resistance and metastasis.

BACKGROUND: METTL3 is an RNA methyltransferase that mediates m6A modification and is implicated in mRNA biogenesis, decay, and translation. However, the biomechanism through which METTL3 regulates MALAT1-miR-1914-3p-YAP axis activity to induce NSCLC drug resistance and metastasis is not very clear. METHODS: The expression of mRNA was analyzed by qPCR assays. Protein levels were analyzed by western blotting and immunofluorescent staining. Cellular proliferation was detected by CCK8 assays. Cell migration and invasion were analyzed by wound healing and transwell assays, respectively. Promoter activities and gene transcription were analyzed by luciferase reporter assays. Finally, m6A modification was analyzed by MeRIP. RESULTS: METTL3 increased the m6A modification of YAP. METTL3, YTHDF3, YTHDF1, and eIF3b directly promoted YAP translation through an interaction with the translation initiation machinery. Moreover, the RNA level of MALAT1 was increased due to a higher level of m6A modification mediated by METTL3. Meanwhile, the stability of MALAT1 was increased by METTL3/YTHDF3 complex. Additionally, MALAT1 functions as a competing endogenous RNA that sponges miR-1914-3p to promote the invasion and metastasis of NSCLC via YAP. Furthermore, the reduction of YAP m6A modification by METTL3 knockdown inhibits tumor growth and enhances sensitivity to DDP in vivo. CONCLUSION: Results indicated that the m6A mRNA methylation initiated by METTL3 promotes YAP mRNA translation via recruiting YTHDF1/3 and eIF3b to the translation initiation complex and increases YAP mRNA stability through regulating the MALAT1-miR-1914-3p-YAP axis. The increased YAP expression and activity induce NSCLC drug resistance and metastasis.