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Metastasis and chemoresistance are major causes of poor prognosis in patients with esophageal squamous cell carcinoma (ESCC), manipulated by multiple factors including deubiquitinating enzyme (DUB). DUB PSMD14 is reported to be a promising therapeutic target in various cancers. Here, we explored the antitumor activity of Thiolutin (THL), the PSMD14 inhibitor, as a new therapy strategy in ESCC. Methods: Through 4-NQO-induced murine ESCC model, we investigated the expression of PSMD14 in esophageal tumorigenesis. Ubiquitin-AMC assay was performed to evaluate DUB activity of PSMD14 with THL treatment. The effect of THL on epithelial-to-mesenchymal transition (EMT), invasion, stemness and chemosensitivity was detected by using in vitro and in vivo experiments. Immunoprecipitation and in vivo ubiquitination assay were conducted to examine whether THL could impair the deubiquitination and stability of SNAIL regulated by PSMD14. Results: Compared with normal esophageal epithelium, PSMD14 was upregulated in 4-NQO-induced murine esophageal epithelium dysplasia and ESCC tissues. THL could significantly weaken DUB activity of PSMD14. Furthermore, the results of in vitro and in vivo assays showed that THL efficiently suppressed motility and stemness and increased sensitivity to cisplatin in ESCC. Mechanically, THL impaired the interaction between PSMD14 and SNAIL, then promoted the ubiquitination and degradation of SNAIL to inhibit EMT which plays a crucial role in ESCC metastasis, stemness and chemosensitivity. TCGA database analysis revealed that high concomitant PSMD14/SNAIL expression predicted shorter overall survival in esophageal cancer. Conclusion: Our findings demonstrate for the first time that suppression of PSMD14/SNAIL axis by THL could be a novel and promising therapeutic approach for ESCC clinical therapy.

The Delphian lymph node (DLN), also known as the prelaryngeal node, is one component of the central lymph node. The DLN has been well studied in laryngeal cancer, although its significance in papillary thyroid cancer (PTC) remains unclear. We retrospectively analyzed 936 patients with PTC who underwent thyroidectomy by a single surgeon in Tianjin Cancer Hospital from 2017 to 2019. Moreover, 250 PTC patients who underwent thyroidectomy by another surgeon in Tianjin Cancer Hospital from January 2019 to April 2019 were used as a validation cohort. Among the 936 patients with PTC, 581 patients (62.1%) had DLNs, of which 177 samples with metastasis (177/581, 30.5%) were verified. DLN metastasis was significantly correlated with sex, age, tumor size, bilateral cancer, multifocality, extrathyroidal extension, lymphovascular invasion and central and lateral neck lymph node metastasis. Multivariate analysis revealed that independent risk factors for DLN metastasis included age, gender, tumor size, extrathyroid extension, lymphovascular invasion and central lymph node metastasis, which determined the nomogram. In particular, tumor size was proven to be one of the most predominant single predictors. The diagnostic model had an area under the curve (AUC) of 0.829 (95% confidence interval, 0.804–0.854). The internal and external validations of the nomogram were 0.819 and 0.745, respectively. Our results demonstrate that DLN metastasis appears to be a critical parameter for predicting metastatic disease of the central compartments. Furthermore, this study provides a precise criterion for assessing DLN metastasis and has great clinical significance for treating PTC.

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Background Deubiquitinating enzymes (DUBs) play critical roles in various cancers by modulating functional proteins post-translationally. Previous studies have demonstrated that DUB Josephin Domain Containing 1 (JOSD1) is implicated in tumor progression, however, the role and mechanism of JOSD1 in head and neck squamous cell carcinoma (HNSCC) remain to be explored. In this study, we aimed to identify the clinical significance and function of JOSD1 in HNSCC. Methods The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were analyzed to find novel DUBs in HNSCC. Immunohistochemistry assay was performed to determine the expression of JOSD1 in our cohort of 42 patients suffered with HNSCC. Kaplan–Meier analysis was used to identify the correlation between JOSD1 and the prognosis of HNSCC patients. The regulation of BRD4 on JOSD1 was determined by using pharmacological inhibition and gene depletion. The in vitro and in vivo experiments were conducted to elucidate the role of JOSD1 in HNSCC. Results The results of IHC showed that JOSD1 was aberrantly expressed in HNSCC specimens, especially in the chemoresistant ones. The overexpression of JOSD1 indicated poor clinical outcome of HNSCC patients. Moreover, JOSD1 depletion dramatically impaired cell proliferation and colony formation, and promoted cisplatin-induced apoptosis of HNSCC cells in vitro. Additionally, JOSD1 suppression inhibited the tumor growth and improved chemosensitivity in vivo. The epigenetic regulator BRD4 contributed to the upregulation of JOSD1 in HNSCC. Conclusions These results demonstrate that JOSD1 functions as an oncogene in HNSCC progression, and provide a promising target for clinical diagnosis and therapy of HNSCC.