\n Purpose: To elucidate mechanisms of thymic epithelial tumor (TET) canceration through characterization of genomic mutations and signal pathway alterations.Methods: Primary tumor and blood samples were collected from 21 patients diagnosed with TETs (thymoma and thymic cancer), 15 of whom were screened by nucleic acid extraction and total exon sequencing. Bioinformatics was used to comprehensively analyze sequencing data for these samples, including differences in tumor mutation burden (TMB) and signaling pathways.Results: We found that the gene with the highest mutation frequency in thymic carcinoma was ZNF429 (36%). In addition, mutations in BAP1 (14%), ABI1 (7%), BCL9L (7%), CHEK2 (7%) were only detected in thymic carcinoma, whereas ZNF721 mutations (7%) were found only in thymoma. Mean TMB values for thymic carcinoma and thymoma groups were 0.722 and 0.663 mutations per megabase (Mb), respectively, differences that were not statistically significant. There were significant differences in enriched pathways for cellular components between tumor metastasis and non-metastatic samples. The ErbB signaling pathway was enriched in both the thymoma group and the intersection group, whereas “pathways in cancer” was found in both the thymoma group and thymic cancer group. In contrast, enrichment of longevity-regulating and MAPK signaling pathways was found only in the thymoma group.Conclusions: We identified multiple differences in somatic genes and pathways, providing insights into differences between thymoma and thymic carcinoma that could aid in designing personalized clinical therapy.

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Characteristics of Genomic Mutations and Signaling Pathway Alterations in Thymic Epithelial Tumors

Pancreatic cancer (PC) is one of the most malignant types of cancer, and is characterized by early metastasis, limited response to chemotherapeutics, and poor prognosis. Therefore, there is an urgent need to explore new therapeutic strategies for PC treatment. Human rhomboid-like 2 (RHBDL2) is differentially expressed in cervical and breast cancer. However, the correlation between RHBDL2 and PC remains unclear. We found that RHBDL2 is highly expressed in human PC cells and tissues and is significantly associated with distant metastasis and poor survival of patients with PC. Gain- and loss-of-function assays indicated that RHBDL2 could accelerate PC cell proliferation and mobility in vitro and in vivo. The RNA-Seq results suggest that RHBDL2 may be involved in the activation of Notch signaling pathway. IMR-1 could restore the proliferation and metastatic capacity of PC cells mediated by RHBDL2. RHBDL2 interacted with and cleaved Notch1, resulting in the release of N1ICD. RHBDL2 decreased the ubiquitination level of N1ICD and collaborated with Ovarian tumor domain-containing 7B (OTUD7B) to stabilize N1ICD via the ubiquitin-proteasome pathway. RHBDL2 facilitated PC cell proliferation and mobility by stabilizing the N1ICD via the OTUD7B and activating the Notch signaling pathway. Thus, targeting this novel pathway may be a potential therapeutic strategy for PC. 

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RHBDL2 promotes the proliferation, migration, and invasion of pancreatic cancer by stabilizing the N1ICD via the OTUD7B and activating the Notch signaling pathway

Lung cancer is the common malignant tumor with the highest mortality rate. Lung cancer patients have achieved benefits from immunotherapy, including immune checkpoint inhibitors (ICIs) therapy. Unfortunately, cancer patients acquire adaptive immune resistance, leading to poor prognosis. Tumor microenvironment (TME) has been demonstrated to play a critical role in participating in acquired adaptive immune resistance. TME is associated with molecular heterogeneity of immunotherapy efficacy in lung cancer. In this article, we discuss how immune cell types of TME are correlated with immunotherapy in lung cancer. Moreover, we describe the efficacy of immunotherapy in driven gene mutations in lung cancer, including KRAS, TP53, EGFR, ALK, ROS1, KEAP1, ZFHX3, PTCH1, PAK7, UBE3A, TNF-α, NOTCH, LRP1B, FBXW7, and STK11. We also emphasize that modulation of immune cell types of TME could be a promising strategy for improving adaptive immune resistance in lung cancer. 

https://www.frontiersin.org/articles/10.3389/fphar.2023.1132158/pdf

Targeting immune cell types of tumor microenvironment to overcome resistance to PD-1/PD-L1 blockade in lung cancer

MiRNA-375 has been reported to play critical roles in a variety of cancers. To unravel its biological roles, especially its specific mechanisms of action in lung squamous cell carcinoma (LUSC), LUSC tissue microarrays and miRNAscope were performed to identify the miR-375 expression. Associations with clinicopathologic features, survival, and the prognostic value of miR-375 in LUSC were clarified in a retrospective study of 90 pairs of LUSC tissues. In vitro and in vivo gain- and loss-of-function assays were conducted to validate the effects and mechanism of miR-375 in LUSC. The mechanism responsible for interactions was verified by dual-luciferase reporter gene assay, immunoprecipitation (IP) analysis, immunofluorescence (IF) assay and ubiquitination assay. We found that miR-375 had higher expression in noncancerous adjacent tissues than in LUSC tissues. Clinicopathologic analyses showed that miR-375 expression was correlated with pathologic stage and was an independent predictor of overall survival (OS) for LUSC. MiR-375, as a tumor inhibitor, inhibited proliferation and metastasis while promoting apoptosis of LUSC cells. Mechanistic research indicated that miR-375 targeted ubiquitin-protein ligase E3A (UBE3A), which in turn promoted the activity of the ERK signaling pathway via ubiquitin-mediated dual-specificity protein phosphatase 1 (DUSP1) degradation. Collectively, we propose a novel mechanism of tumorigenesis and metastasis of LUSC via the miR-375/UBE3A/DUSP1/ERK axis, which could potentially facilitate new strategies for the treatment of LUSC. 

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MicroRNA-375 restrains the progression of lung squamous cell carcinoma by modulating the ERK pathway via UBE3A-mediated DUSP1 degradation

Incidental finding of undiagnosed aortic coarctation in an elderly patient with a rare association with thymic carcinoma: a case report with review of the literature

Background: Esophageal cancer is the sixth-most common fatal malignant tumor worldwide. Little is known regarding the genetic drivers that influence targeted therapy outcomes in patients with esophageal cancer. Exploring the pathogenesis of this lethal tumor could provide clues for developing appropriate therapeutic drugs. Ubiquitin-protein ligase E3A (UBE3A) reportedly promotes or suppresses various types of malignant tumors. However, the cancer-related role of UBE3A in esophageal cancer remains unclear. Methods: The relationship of UBE3A with the clinicopathological features of pancreatic tumors was bioinformatically investigated in the TCGA dataset. The protein levels of UBE3A and ZNF185 were assessed by Western blot and immunohistochemistry. The role of UBE3A and ZNF185 in esophageal cancer growth was assessed by MTS assays, colony formation assays, and experiments in mouse xenograft models. The interaction between UBE3A and ZNF185 was investigated by co-immunoprecipitation. The relationship between UBE3A, ZNF185, and NOTCH signaling pathway was explored by Western blot and quantitative real-time PCR. Results: We found that UBE3A was upregulated in patients with esophageal cancer and enhanced the cellular progression of esophageal cancer. Moreover, we found that UBE3A degraded ZNF185 in esophageal cancer. Additionally, ZNF185 suppressed the progression of esophageal cancer by inactivating the NOTCH pathway. Conclusions: These data demonstrated that aberrant expression of UBE3A led to enhanced progression of esophageal cancer through the ZNF185/NOTCH signaling axis. Therefore, UBE3A might be an ideal therapeutic candidate for esophageal cancer.

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UBE3A activates the NOTCH pathway and promotes esophageal cancer progression by degradation of ZNF185

Background Thymoma is the most common tumor within the anterior mediastinum though it is still a rare tumor disease. Surgery is considered to be one of the most important treatment methods for it, while radiotherapy and platinum-based chemotherapy are also in use. Based on the Surveillance, Epidemiology and End Results (SEER) database, we conducted our research and determined the value of operation in the treatment of thymoma. Methods In total, 1,587 patients with thymoma were selected out from the database. We grouped them according to type and stage of thymoma. We used cox-regression analysis to selected meaningful factors. Kaplan-Meier method was used for survival analysis. Results The mean survival times of patients with type A, B, C thymoma were 130.79, 123.81, 77.18 months orderly. Among all 1,587 patients, the mean survival time of those treated with surgery was 124.92 months, while it was 65.03 months for those without surgery treatment (P<0.05). Within each group of patients with the same kind of and same stage thymoma, who got surgical treatment had a longer survival period (P<0.05). Conclusions Type c thymoma had the worst prognosis. Patients who received surgical treatment had longer survival time. And it didn’t matter what type or what stage of thymoma.

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Zhikun Zheng

Papers

UBE3A activates the NOTCH pathway and promotes esophageal cancer progression by degradation of ZNF185

Prolonged survival time with surgical therapy in different types of thymoma: an analysis based on Surveillance Epidemiology and End Results Database