Circ_0020256 induces fibroblast activation to drive cholangiocarcinoma development via recruitment of EIF4A3 protein to stabilize KLF4 mRNA.

Cancer-associated fibroblasts (CAFs) are a kind of stromal cells in the cholangiocarcinoma (CCA) microenvironment, playing crucial roles in cancer development. However, the potential mechanisms of the interaction between CCA cells and CAFs remain obscure. This work investigated the role of circ_0020256 in CAFs activation. We proved circ_0020256 was up-regulated in CCA. High circ_0020256 expression facilitated TGF-ß1 secretion from CCA cells, which activated CAFs via the phosphorylation of Smad2/3. Mechanistically, circ_0020256 recruited EIF4A3 protein to stabilize KLF4 mRNA and upregulate its expression, then KLF4 bound to TGF-ß1 promoter and induced its transcription in CCA cells. KLF4 overexpression abrogated the inhibition of circ_0020256 silencing in TGF-ß1/Smad2/3-induced CAFs activation. Furthermore, CCA cell growth, migration, and epithelial-mesenchymal transition were favored by CAFs-secreted IL-6 via autophagy inhibition. We also found circ_0020256 accelerated CCA tumor growth in vivo. In conclusion, circ_0020256 promoted fibroblast activation to facilitate CCA progression via EIF4A3/KLF4 pathway, providing a potential intervention for CCA progression.

Immunogenic cell death-associated biomarkers classification predicts prognosis and immunotherapy efficacy in pancreatic ductal adenocarcinoma.

Introduction: Immunogenic cell death (ICD) is a sort of regulated cell death (RCD) sufficient to trigger an adaptive immunological response. According to the current findings, ICD has the capacity to alter the tumor immune microenvironment by generating danger signals or damage-associated molecular patterns (DAMPs), which may contribute in immunotherapy. It would be beneficial to develop ICD-related biomarkers that classify individuals depending on how well they respond to ICD immunotherapy. Methods and results: We used consensus clustering to identify two ICD-related groupings. The ICD-high subtype was associated with favorable clinical outcomes, significant immune cell infiltration, and powerful immune response signaling activity. In addition, we developed and validated an ICD-related prognostic model for PDAC survival based on the tumor immune microenvironment. We also collected clinical and pathological data from 48 patients with PDAC, and patients with high EIF2A expression had a poor prognosis. Finally, based on ICD signatures, we developed a novel PDAC categorization method. This categorization had significant clinical implications for determining prognosis and immunotherapy. Conclusion: Our work emphasizes the connections between ICD subtype variations and alterations in the immune tumor microenvironment in PDAC. These findings may help the immune therapy-based therapies for patients with PDAC. We also created and validated an ICD-related prognostic signature, which had a substantial impact on estimating patients' overall survival times (OS).

Correction: Zheng et al. Glycolysis-Related SLC2A1 Is a Potential Pan-Cancer Biomarker for Prognosis and Immunotherapy. Cancers 2022, 14, 5344.

The authors wish to make the following corrections to this paper [...].

SHH/GLI2-TGF-ß1 feedback loop between cancer cells and tumor-associated macrophages maintains epithelial-mesenchymal transition and endoplasmic reticulum homeostasis in cholangiocarcinoma.

BACKGROUND: Tumor-associated macrophages (TAMs) play a dual role in tumors. However, the factors which drive the function of TAMs in cholangiocarcinoma remain largely undefined. METHODS: SHH signaling pathway and endoplasmic reticulum stress (ERS) indicators were detected in clinical tissues and cholangiocarcinoma cell lines. TAMs were co-cultured with cholangiocarcinoma cells under conditions of hypoxia/normoxia. Polarized TAMs were counted by flow cytometry, and TGF-ß1 levels in cell supernatants were detected by ELISA. The effects of glioma-associated oncogene GLI2 on TAMs themselves and cholangiocarcinoma cells were examined by conducting interference and overexpression assays. RESULTS: The SHH signaling pathway and ERS were both activated in tumor tissues or tumor cell lines under conditions of hypoxia. In co-culture experiments, the presence of cholangiocarcinoma cells increased the proportion of M2-polarized TAMs and the secretion of TGF-ß1 by TAMs, while knockdown of SHH expression reversed those increases. Overexpression of GLI2 in TAMS or stimulation of TAMS with Hh-Ag1.5 increased their levels of TGF-ß1 expression. Furthermore, under co-culture conditions, interference with GLI2 expression in TAMs reduced the tumor cell migration, invasion, and ER homeostasis induced by Hh-Ag1.5-pretreated TAMs. Under conditions of hypoxia, the presence of cholangiocarcinoma cells promoted the expression of GLI2 and TGF-ß1 in Tams, and in turn, TAMs inhibited the apoptosis and promoted the migration and invasion of cholangiocarcinoma cells. In vivo, an injection of cholangiocarcinoma cells plus TAMs contributed to the growth, EMT, and ER homeostasis of tumor tissue, while an injection of TAMs with GLI2 knockdown had the opposite effects. CONCLUSION: Cholangiocarcinoma cells regulated TAM polarization and TGF-ß1 secretion via a paracrine SHH signaling pathway, and in turn, TAMs promoted the growth, EMT, and ER homeostasis of cholangiocarcinoma cells via TGF-ß1.

Glycolysis-Related SLC2A1 Is a Potential Pan-Cancer Biomarker for Prognosis and Immunotherapy.

SLC2A1 plays a pivotal role in cancer glycometabolism. SLC2A1 has been proposed as a putative driver gene in various cancers. However, a pan-cancer analysis of SLC2A1 has not yet been performed. In this study, we explored the expression and prognosis of SLC2A1 in pan-cancer across multiple databases. We conducted genetic alteration, epigenetic, and functional enrichment analyses of SLC2A. We calculated the correlation between SLC2A1 and tumor microenvironment using the TCGA pan-cancer dataset. We observed high expression levels of SLC2A1 with poor prognosis in most cancers. The overall genetic alteration frequency of SLC2A1 was 1.8% in pan-cancer, and the SLC2A1 promoter was hypomethylation in several cancers. Most m6A-methylation-related genes positively correlated with the expression of SLC2A1 in 33 TCGA cancers. Moreover, SLC2A1 was mainly related to the functions including epithelial-mesenchymal transition, glycolysis, hypoxia, cell-cycle regulation, and DNA repair. Finally, SLC2A1 positively associated with neutrophils and cancer-associated fibroblasts in the tumor microenvironment of most cancers and significantly correlated with TMB and MSI in various cancers. Notably, SLC2A1 was remarkably positively correlated with PD-L1 and CTLA4 in most cancers. SLC2A1 might serve as an attractive pan-cancer biomarker for providing new insights into cancer therapeutics.

Giant recurrent left inguinal hernia with femoral nerve injury: a report of a rare case.

BACKGROUND: Giant inguinal hernia(GIH), a rare disease, has brought great challenges to surgeons. GIH is defined as an inguinal hernia that extends below the midpoint of the inner thigh in standing position. However, a giant recurrent inguinal hernia resulting from previous operations that destroy the anatomical structure of the inguinal region is extremely rare. Nerve injury, a complication following inguinal hernia repair, is mostly found in ilioinguinal nerve and iliohypogastric nerve, which often presents as numbness and acute or chronic pain, while postoperative muscular dysfunction results from femoral nerve injury is rare. CASE PRESENTATION: A 77-years-old woman presented with a complaint of a reducible mass in the left inguinal of duration 1 year. The patient had three previous inguinal hernia repairs. Physical examination and auxiliary examination indicated a giant inguinal hernia with femoral nerve injury. After preoperative evaluation and preparation, a transabdominal partial extraperitoneal(TAPE) repair have performed. Finally, the patient recovered and was discharged. CONCLUSIONS: In conclusion, we reported a rare case of a giant recurrent inguinal hernia with femoral nerve injury and made a successful treatment for the patient via transabdominal partial extraperitoneal(TAPE) repair.

Primary gastric melanoma in a young woman: A case report.

BACKGROUND: Most melanomas identified in the stomach are metastatic. The primary gastric melanoma (PGM) is extremely rare. As such, clinical reports of PGM are scarce in the literature, lending to the challenge of diagnosis and treatment. CASE SUMMARY: A 31-year-old woman presented with a 1-mo history of dysphagia but no symptoms of abdominal pain, abdominal distension, nausea, vomiting, hematemesis, or melena. The patient reported an unintentional weight loss of 6 kg within that time. History-taking revealed no previous medical conditions or surgical events. Abdominal computed tomography at a local hospital had suggested gastric tumor. Endoscopic examination in our hospital found a large, irregular, black mass. Subsequent laparoscopic exploration found the tumor on the side of the stomach fundus penetrating through the serosa, and enlarged lymph nodes (groups 1, 3, 7, and 9) fused into a mass, surrounding the peripheral artery and inseparable. Postoperative immunohistochemistry suggested gastric malignant melanoma. Positron emission tomography-computed tomography confirmed PGM. Treatment with programmed cell death protein 1 antagonist (toripalimab) plus chemotherapy (paclitaxel) was initiated but discontinued upon tumor bleeding. At the last telephone follow-up, the patient reported poor general condition but was alive. CONCLUSION: Although unresolved and ongoing, this rare case of PGM expands the overall knowledge about this rare tumor's diagnosis and management.