IGF-1-mediated FOXC1 overexpression induces stem-like properties through upregulating CBX7 and IGF-1R in esophageal squamous cell carcinoma.

Substantial evidence attests to the pivotal role of cancer stem cells (CSC) in both tumorigenesis and drug resistance. A member of the forkhead box (FOX) family, FOXC1, assumes significance in embryonic development and organogenesis. Furthermore, FOXC1 functions as an overexpressed transcription factor in various tumors, fostering proliferation, enhancing migratory capabilities, and promoting drug resistance, while maintaining stem-cell-like properties. Despite these implications, scant attention has been devoted to its role in esophageal squamous cell carcinoma. Our investigation revealed a pronounced upregulation of FOXC1 expression in ESCC, correlating with a poor prognosis. The downregulation of FOXC1 demonstrated inhibitory effects on ESCC tumorigenesis, proliferation, and tolerance to chemotherapeutic agents, concurrently reducing the levels of stemness-related markers CD133 and CD44. Further studies validated that FOXC1 induces ESCC stemness by transactivating CBX7 and IGF-1R. Additionally, IGF-1 activated the PI3K/AKT/NF-κB and MEK/ERK/NF-κB pathways through its binding to IGF-1R, thereby augmenting FOXC1 expression. Conversely, suppressing FOXC1 impeded ESCC stemness induced by IGF-1. The presence of a positive feedback loop, denoted by IGF-1-FOXC1-IGF-1R, suggests the potential of FOXC1 as a prognostic biomarker for ESCC. Taken together, targeting the IGF-1-FOXC1-IGF-1R axis emerges as a promising approach for anti-CSC therapy in ESCC.

TRPM8 inhibits substance P release from primary sensory neurons via PKA/GSK-3beta to protect colonic epithelium in colitis.

Transient receptor potential melastatin 8 (TRPM8) is a cold sensory receptor in primary sensory neurons that regulates various neuronal functions. Substance P (SP) is a pro-inflammatory neuropeptide secreted by the neurons, and it aggravates colitis. However, the regulatory role of TRPM8 in SP release is still unclear. Our study aimed to investigate TRPM8's role in SP release from primary sensory neurons during colitis and clarify the effect of SP on colonic epithelium. We analyzed inflammatory bowel disease patients' data from the Gene Expression Omnibus dataset. Dextran sulfate sodium (DSS, 2.5%)-induced colitis in mice, mouse dorsal root ganglion (DRG) neurons, ND7/23 cell line, and mouse or human colonic organoids were used for this experiment. Our study found that TRPM8, TAC1 and WNT3A expression were significantly correlated with the severity of ulcerative colitis in patients and DSS-induced colitis in mice. The TRPM8 agonist (menthol) and the SP receptor antagonist (Aprepitant) can attenuate colitis in mice, but the effects were not additive. Menthol promoted calcium ion influx in mouse DRG neurons and inhibited the combination and phosphorylation of PKAca from the cAMP signaling pathway and GSK-3ß from the Wnt/ß-catenin signaling pathway, thereby inhibiting the effect of Wnt3a-driven ß-catenin on promoting SP release in ND7/23 cells. Long-term stimulation with SP inhibited proliferation and enhanced apoptosis in both mouse and human colonic organoids. Conclusively, TRPM8 inhibits SP release from primary sensory neurons by inhibiting the interaction between PKAca and GSK-3ß, thereby inhibiting the role of SP in promoting colonic epithelial apoptosis and relieving colitis.

IGF1R-phosphorylated PYCR1 facilitates ELK4 transcriptional activity and sustains tumor growth under hypoxia.

The proline synthesis is importantly involved in tumor growth under hypoxia, while the underlying mechanism remains to be further investigated. Here we show that pyrroline-5-carpoxylate reductase-1 (PYCR1), displaying a constant nuclear localization, is phosphorylated by nuclear IGF1R at Tyrosine 135 under hypoxia; this phosphorylation promotes the binding of PYCR1 to ELK4 and thus PYCR1 recruitment to ELK4-targeted genes promoter. Under hypoxia, ELK4-binding ability and enzymatic activity of PYCR1 are both required for ELK4-Sirt7-mediated transcriptional repression and cell growth maintenance, in which PYCR1-catalyzed NAD+ production stimulates the deacetylation activity of Sirt7 on H3K18ac that restrains genes transcription. Functionally, PYCR1 Tyr-135 phosphorylation exerts supportive effect on tumor growth under hypoxia, and the level of PYCR1 Tyr-135 phosphorylation is associated with malignancy of colorectal cancer (CRC). These data uncover the relationship between the compartmentally metabolic activity of PYCR1 and genes transcription regulation, and highlight the oncogenic role of PYCR1 during CRC development.

TAOK3 Facilitates Esophageal Squamous Cell Carcinoma Progression and Cisplatin Resistance Through Augmenting Autophagy Mediated by IRGM.

Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers because of its robust aggressive phenotype and chemoresistance. TAO kinase belongs to mitogen-activated protein kinases, which mediate drug resistance in multiple cancers. However, the role of TAO kinase in ESCC progression and chemoresistance has never been explored. Here, it is reported that TAOK3 augments cell autophagy and further promotes ESCC progression and chemoresistance. Mechanistically, TAOK3 phosphorylates KMT2C at S4588 and strengthens the interaction between KMT2C and ETV5. Consequently, the nuclear translocation of KMT2C is increased, and the transcription of autophagy-relevant gene IRGM is further upregulated. Additionally, the inhibitor SBI-581 can significantly suppress cell autophagy mediated by TAOK3 and synergizes with cisplatin to treat ESCC in vitro and in vivo.

Transcription factor 3 promotes migration and invasion potential and maintains cancer stemness by activating ID1 expression in esophageal squamous cell carcinoma.

Transcription factor 3 (TCF3) is a member of the basic Helix - Loop - Helix (bHLH) transcription factor (TF) family and is encoded by the TCF3 gene (also known as E2A). It has been shown that TCF3 functions as a key transcription factor in the pathogenesis of several human cancers and plays an important role in stem cell maintenance and carcinogenesis. However, the effect of TCF3 in the progression of esophageal squamous cell carcinoma (ESCC) is poorly known. In our study, TCF3 was found to express highly and correlated with cancer stage and prognosis. TCF3 was shown to promote ESCC invasion, migration, and drug resistance both from the results of in vivo and in vitro assays. Moreover, further studies suggested that TCF3 played these roles through transcriptionally regulating Inhibitor of DNA binding 1(ID1). Notably, we also found that TCF3 or ID1 was associated with ESCC stemness. Furthermore, TCF3 was correlated with the expression of cancer stemness markers CD44 and CD133. Therefore, maintaining cancer stemness might be the underlying mechanism that TCF3 transcriptionally regulated ID1 and further promoted ESCC progression and drug resistance.

Targeting IGF1R signaling enhances the sensitivity of cisplatin by inhibiting proline and arginine metabolism in oesophageal squamous cell carcinoma under hypoxia.

BACKGROUND: Cisplatin (DDP)-based chemotherapy is commonly adopted as the first-line treatment for patients with oesophageal squamous cell carcinoma (OSCC), but the high rate of drug resistance limits its clinical application and the underlying mechanisms at play remain unclear. The aims of this study were to elucidate the role of abnormal signal transmission and metabolism in the chemoresistance of OSCC under hypoxia and to identify targeted drugs that enhance the sensitivity of DDP chemotherapy. METHODS: Upregulated genes in OSCC were determined by RNA sequencing (RNA-seq), the Cancer Genome Atlas (TCGA) database, immunohistochemistry (IHC), real-time quantitative PCR (RT-qPCR), and western blotting (WB). The clinicopathological significance of insulin-like growth factor-I receptor (IGF1R), argininosuccinate synthetase 1 (ASS1), and pyrroline-5-carboxylate reductase 1 (PYCR1) in OSCC was analysed using tissue micriarray (TMA). Metabolic abnormalities were determined by untargeted metabolomics analysis. The DDP-resistance role of IGF1R, ASS1, and PYCR1 in OSCC was investigated in vitro and in vivo. RESULTS: Generally, tumour cells exist in a hypoxic microenvironment. By genomic profiling, we determined that IGF1R, as a receptor tyrosine kinase (RTK), was upregulated in OSCC under low-oxygen conditions. Clinically, enhanced IGF1R expression was associated with higher tumour stages and a poorer prognosis in OSCC patients, and its inhibitor, linsitinib, showed synergistic effects with DDP therapy in vivo and in vitro. Since oxygen-deprivation frequently lead to metabolic reprogramming, we further learned via metabolomics analysis that abnormal IGF1R pathways promoted the expression of metabolic enzymes ASS1 and PYCR1 by the transcriptional activity of c-MYC. In detail, enhanced expression of ASS1 promotes arginine metabolism for biological anabolism, whereas PYCR1 activates proline metabolism for redox balance, which maintains the proliferation ability of OSCC cells during DDP treatment under hypoxic conditions. CONCLUSION: Enhanced expression of ASS1 and PYCR1 via IGF1R pathways rewired arginine and proline metabolism, promoting DDP resistance in OSCC under hypoxia. Linsitinib targeting IGF1R signaling may lead to promising combination therapy options for OSCC patients with DDP resistance.

Global Trends and Hotspots of Transient Receptor Potential Melastatin 8 Research from 2002 to 2021: A Bibliometric Analysis.

Background: Transient receptor potential channels are the major temperature and nociceptive receptors in the human body and transient receptor potential melastatin 8 (TRPM8) is the cold-sensitive and non-selective cation channel. In our study, we performed a bibliometric analysis of TRPM8 from 2002 to 2021 to summarize the current research status and potential research direction in the future. Methods: The TRPM8-related publications were selected from the Web of Science Core Collection SCI-EXPANDED database from 2002 to 2021. The publication details, such as authors, titles, and author keywords, were used for bibliometric analysis and network visualization to present the current state of TRPM8 research. Results: A total of 1035 articles met the inclusion criteria. The number of TRPM8-related articles has grown rapidly over the past two decades. The USA has the largest number of publications, citations, and international collaborations. The TRPM8-related articles are mainly published and cited in neurological journals, such as the Journal of Neuroscience (41 publications and 2171 local citations). Prevarskaya N. has the most publications (26), and Patapoutian A. has been cited the most (1414 local citations). The popular disciplines in TRPM8 research include Neurosciences and Neurology, Pharmacology and Pharmacy, Biochemistry, and Molecular Biology. Research hotspots are mainly TRP channel, calcium, prostate cancer, proliferation, pain, cold, nociception, and inflammation. Conclusion: Our bibliometric analysis demonstrates that the number of TRPM8 studies has increased from 2002 to 2021. The global research trends and hotspots include the activation mechanism of TRPM8 in neurons, the role of TRPM8 in neuronal and non-neuronal diseases, and therapeutic target research.

The influences of timing of urgent endoscopy in patients with acute variceal bleeding: a cohort study.

BACKGROUND: There has always been a debate on the optimal timing of endoscopy in patients with acute variceal bleeding (AVB). OBJECTIVE: This study aimed to examine the relation between the timing of endoscopy and the short-term outcomes of patients with AVB. METHODS: Patients with AVB who underwent endoscopy within 24 h after admission at our tertiary care center from 2014 to 2022 were evaluated retrospectively. The primary outcomes were the 6-week mortality and re-bleeding. The secondary outcomes included the total number of blood units transfused, the length of hospital stay, and the need for salvage therapy. We used Cox proportional hazards model to analyze the predictors of 6-week mortality in all patients as well as in those who were at high risk of further bleeding or death. RESULTS: A total of 312 patients were enrolled. Among them, 170 patients (54.49%) underwent urgent endoscopy (< 6 h), and 142 patients (45.51%) underwent early endoscopy (6-24 h). There were no significant differences between the urgent-endoscopy group and the early-endoscopy group, regarding the 6-week mortality (16.47% vs. 10.56%; P value = 0.132) and 6-week re-bleeding rate (11.2% vs. 16.2%; P value = 0.196). In multivariate analysis, time to endoscopy was independent of 6-week mortality (P value = 0.170), but the time between the beginning of bleeding and endoscopy (within 12 h) was significantly associated with low 6-week mortality (OR: 0.16; 95% CI: 0.06-0.46; P value = 0.001). Time to endoscopy was still not associated with 6-week mortality in patients at high risk for further bleeding or death (Glasgow-Blatchford score ≥ 12, n = 138, P value = 0.902). CONCLUSIONS: Endoscopy performed within 6 h of admission, rather than within 6 to 24 h, did not improve six-week clinical outcomes in patients in stable condition with AVB and even those who were at high risk of further bleeding and death.

Global research trend of esophageal squamous cell carcinoma from 2012 to 2022: a bibliometric analysis.

Background: Esophageal cancer is currently a worldwide health problem. Esophageal squamous cell carcinoma (ESCC) is the most common pathological type of esophageal cancer, and its treatment methods and therapeutic effects are relatively limited, so it also requires the unremitting efforts of basic and clinical researchers to overcome difficulties. Bibliometric analysis can help sort out global research trends and hotspots, but no bibliometric analysis of ESCC has been reported. Therefore, we performed this study to analyze the global trends and potential hotspots of ESCC to indicate future research directions. Methods: The articles related to ESCC research were collected from the WoS Core Collection SCI-EXPANDED database from 2012 to 2022. The article information was analyzed by BiblioShiny and VOSviewer. Results were presented as bar and network visualization to describe the current trend of ESCC research. This was a retrospective study evaluating data that is publicly available online and at libraries and institutional review board approval, as such, was not demanded. Results: The global publication trend illustrated a strong growth in the ESCC research field (annual growth rate of 11.4%) and the citation trend increased from an average of 2.98 citations per article per year in 2012 to an average of 3.84 citations per article per year in 2019. With the corresponding author's country, China contributed the largest number (5,063 articles). The scholars from China and USA had the most collaboration (427 times). China had the largest number of institutions conducting ESCC research. Oncotarget, Oncology Letters, and Annals of Surgical Oncology published the most articles, while Cancer Research, International Journal of Cancer, and Journal of Clinical Oncology had the most local citations. Furthermore, the clinical research hotspots involved in the treatment of ESCC and the basic research hotspots involved in tumor malignant phenotype have received the most attention in recent years. Conclusion: Our study demonstrated that the research of ESCC has developed rapidly in recent years, and the academic institutions in China have played a decisive role in this field. The global research purpose is to find effective therapies against ESCC, so some emerging hotspots related to ESCC treatment, such as endoscopic therapy, chemoradiotherapy, immunotherapy, tumor microenvironment, and the epithelial-mesenchymal transition will receive more attention and develop rapidly in the future.

ETV5 overexpression promotes progression of esophageal squamous cell carcinoma by upregulating SKA1 and TRPV2.

Esophageal squamous cell carcinoma (ESCC) is notorious for the rapid progression especially early tumor metastasis due to the unclear mechanism. Recently, ETV5 attracts much attention for its potential role as an oncogenic transcription factor involved in multiple cancers. However, no one reported the mechanism behind the association between ETV5 expression and esophageal squamous cell carcinoma progression. In this study, we found that ETV5 was upregulated in ESCC both from online database and our ESCC tissues and ETV5 was associated with tumor staging and prognosis. Knockdown of ETV5 or its downstream genes SKA1 and TRPV2 significantly suppress ESCC cells migration and invasion, respectively. Additionally, in vivo study showed knockdown of ETV5 inhibited tumor metastasis. Further experiments unveiled ETV5 could transcriptionally upregulate the expression of SKA1 and TRPV2 and further activate MMPs in ESCC progression. In conclusion, ETV5 was associated with ESCC tumor staging and ESCC prognosis clinically. ETV5 promoted metastasis of ESCC by activating MMPs through augmenting the transcription of SKA1 and TRPV2. ETV5 was likely to be a novel oncogene and therapeutic target in ESCC.

Submucosal Tunneling Endoscopic Resection for Submucosal Tumors in the Proximal Esophagus.

BACKGROUND: Submucosal tunneling endoscopic resection (STER) is widely applied for treatment of gastrointestinal submucosal tumors (SMTs) originating from the muscularis propria layer. However, the tumor location within the proximal esophagus makes STER a challenge for the endoscopists. The aim of this study was to summarize the technique skill and evaluate the outcomes of proximal esophageal STER. STUDY DESIGN: A total of 72 patients with SMTs in the proximal esophagus undergoing STER were included from February 2019 to March 2021. Imaging 3-dimensional reconstruction was used for patients with large SMTs. Clinicopathological, endoscopic, and follow-up data were collected and analyzed. RESULTS: In this study, all the tumors were removed completely and no gross disease was remaining. The en bloc resection was achieved in 90.28% of patients, and the complications rate was 6.95%. Three-dimensional reconstruction was used for 30 patients (41.67%) with large SMTs (transverse diameter >2.0 cm). Based on statistical analysis, tumors with irregular shape and larger size were the significant contributors to piecemeal resection. Larger tumors increase the risk of long operation time, and irregular tumor shapes increase the risk of complications. The median hospitalization time was 4 days. All of the complications were cured by conservative treatment. A median follow-up of 12 months was available, and all patients were free from local recurrence or distant metastasis during the study period. CONCLUSIONS: STER is an effective and safe methodology for the resection of proximal esophageal SMTs. Tumor size and shape mainly impact the piecemeal resection rate, STER-related complications, and procedural difficulty.

A New Preparation Method for Peroral Endoscopic Myotomy in Patients with Achalasia Can Effectively Reduce the Esophageal Residual Contents: A Comparative Retrospective Study.

METHODS: This retrospective study enrolled 65 achalasia patients who underwent POEM from June 2017 to October 2021. Based on the preoperative diet strategies, patients were divided into carbonated beverage group (n = 48) and control group (n = 17). Demographic and clinical data, duration of preoperative endoscopy, quality of esophagus cleansing, and patient satisfaction on preoperative procedure were collected and compared. In the current study, we established the quality of esophagus cleansing: Grade A, no remnants or only liquid or frothy discharge; Grade B, a little amount of solid content remained; and Grade C, a large amount of solid content remained. RESULTS: There were 41 Grade A, 6 Grade B, and 1 Grade C patients in the carbonated beverage group, while there were 8 Grade A, 6 Grade B, and 3 Grade C patients in the control group (p value = 0.001). The esophagus cleansing degrees were significantly ameliorated after drinking carbonated beverages in all the three subtypes of achalasia according to the degree of dilatation. The mean duration of preoperative endoscopy was 6.54 ± 2.250 minutes in the carbonated beverage group and 10.27 ± 4.788 minutes in the control group (p value = 0.010). The score of patient satisfaction concerning the procedure before the POEM in the carbonated beverage group was 4.5 ± 0.652, while the score in the control group was 4.35 ± 0.702 (p value = 0.436). In the multivariate analysis, patient satisfaction was significantly associated with male (odds ratio 0.296, 95% CI: 0.097-0.905, p value = 0.033). CONCLUSIONS: Drinking carbonated beverages reduce the duration of preoperative endoscopy and ameliorate the esophagus cleansing degrees without impairing patient satisfaction.