USP4 promotes the proliferation, migration, and invasion of esophageal squamous cell carcinoma by targeting TAK1.

Ubiquitin-specific protease 4 (USP4) represents a potential oncogene involved in various human cancers. Nevertheless, the biological roles and precise mechanism of USP4 in esophageal squamous cell carcinoma (ESCC) progression are not understood. Here, USP4 expression was found to be markedly upregulated in ESCC tumor tissues and cells. Loss- and gain-of-function assays suggested that USP4 silencing inhibited ESCC cell proliferation, migration, and invasion, while USP4 overexpression promoted these behaviors. Consistently, USP4 silencing repressed tumor growth and metastasis in an ESCC nude mouse model in vivo. As a target molecule of USP4, transforming growth factor-ß-activated kinase 1 (TAK1) also showed high expression in ESCC. Moreover, we observed that USP4 specifically interacted with TAK1 and stabilized TAK1 protein levels via deubiquitination in ESCC cells. Importantly, USP4 promotes ESCC proliferation, migration, and invasion via the MEK/ERK signaling pathway and can be inhibited by U0126. Neutral red (NR), an inhibitor of USP4 can suppress ESCC progression in vitro and in vivo. Overall, this study revealed that USP4/TAK1 plays crucial roles in ESCC progression by modulating proliferation, migration, and invasion, and USP4 might be a potential therapeutic target in ESCC.

High expression of PPFIA1 in human esophageal squamous cell carcinoma correlates with tumor metastasis and poor prognosis.

BACKGROUND: PTPRF interacting protein alpha 1 (PPFIA1) is reportedly related to the occurrence and progression of several kinds of malignancies. However, its role in esophageal squamous cell carcinoma (ESCC) is unclear. This current study investigated the prognostic significance and biological functions of PPFIA1 in ESCC. METHODS: Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), and Gene Expression Omnibus (GEO) were used to investigate PPFIA1 expression in esophageal cancer. The relationship between PPFIA1 expression and clinicopathological characteristics and patient survival was evaluated in GSE53625 dataset, and verified in the cDNA array based on qRT-PCR and tissue microarray (TMA) dataset based on immunohistochemistry. The impact of PPFIA1 on the migration and invasion of cancer cells were investigated by wound-healing and transwell assays, respectively. RESULTS: The expression of PPFIA1 was obviously increased in ESCC tissues versus adjacent esophageal tissues according to online database analyses (all P < 0.05). High PPFIA1 expression was closely related to several clinicopathological characteristics, including tumor location, histological grade, tumor invasion depth, lymph node metastasis, and tumor-node-metastasis (TNM) stage. High PPFIA1 expression was related to worse outcomes and was identified as an independent prognostic factor of overall survival in ESCC patients (GSE53625 dataset, P = 0.019; cDNA array dataset, P < 0.001; TMA dataset, P = 0.039). Downregulation of PPFIA1 expression can significantly reduce the migration and invasion ability of ESCC cells. CONCLUSION: PPFIA1 is related to the migration and invasion of ESCC cells, and can be used as a potential biomarker to evaluate the prognosis of ESCC patients.

Establishment of a risk model by integrating hypoxia genes in predicting prognosis of esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) has a dismal prognosis, and hypoxia plays a key role in metastasis and proliferation of ESCC. Thus, we aimed to develop a hypoxia-based gene signature to assist in the treatment decisions and prognosis. METHODS: We performed consensus clustering analysis on samples from GSE53625 dataset from the Gene Expression Omnibus (GEO) database and used weighted gene co-expression network analysis to filter out candidate modules, which were then intersected with differentially expressed genes from clustered subgroups to obtain hypoxia-related genes (HRGs). After that, the aforementioned genes were used to construct risk score models and validated in The Cancer Genome Atlas (TCGA) database and Cox regression analysis were used to construct a nomogram. Immunohistochemical was used to detect protein expression levels of relevant genes. Moreover, the relationship between risk scores and tumor microenvironment was explored. RESULTS: A hypoxia risk model containing six genes (PNPLA1, CARD18, IL-18, SLC37A2, ADAMTS18, and FAM83C) was constructed by screening key HRGs. Poorer prognosis in the high-risk group than in the low-risk group. And Cox regression analysis showed that risk score was an independent prognostic factor. The nomogram based on risk scores could well predict 1-, 3-, and 5-year survival. P53, Wnt, and hypoxia signaling pathways may be some regulatory mechanisms of hypoxia associated with the tumor microenvironment. In addition, we confirmed the high expression of BGN and low expression of IL-18 in ESCC tissues. CONCLUSIONS: Our study determined the prognostic value of a 6-hypoxia gene signature and a prognostic model, providing potential prognostic predictors and therapeutic targets for ESCC.

Metastasis patterns and prognosis in breast cancer patients aged ≥ 80 years: a SEER database analysis.

Background: This study aimed to investigate the metastasis patterns and prognosis of breast cancer (BC) in patients aged ≥ 80 years with distant metastases, as the current literature lacks studies in this population. Methods: A retrospective, population-based study using data from the Surveillance, Epidemiology, and End Results (SEER) database was conducted to evaluate 36,203 patients with BC from 2010 to 2016. Patients were classified into three groups, the older group (aged ≥ 80 years), middle-aged group (aged 60-79 years), and younger group (aged < 60 years). The role of age at the time of BC diagnosis in metastasis patterns was investigated, and the survival of different age groups of patients with BC was assessed. Results: Overall, 4,359 (12%) patients were diagnosed with BC at age ≥ 80 years, 19,688 (54%) at 60-79 years, and 12,156 (34%) at < 60 years. Compared with the other two groups, those in the older group had a lower rate of treatment acceptance. Statistical analysis revealed that older patients were more likely to have lung invasion only (odds ratio [OR]: 1.274, 95% confidence interval [CI]: 1.163-2.674) and less likely to have bone invasion only (OR: 0.704, 95% CI: 0.583-0.851), brain invasion only (OR: 0.329, 95% CI: 0.153-0.706), or multiple metastatic sites (OR: 0.361, 95% CI: 0.284-0.458) compared to the other two groups. Age at diagnosis was an independent prognostic factor for survival. The older group had the worst overall survival (OS, P<0.001) and BC-specific survival (CSS, P<0.001). Furthermore, patients aged ≥ 80 years with only liver metastasis had the worst CSS and OS. Conclusion: Patients aged ≥ 80 years were less likely to be receptive to cancer-related therapy and had the highest cancer mortality rate among all patients. Our findings will hopefully help clinicians develop more appropriate modalities of cancer treatment in elderly BC patients.