Zinc (Zn) has antioxidant effect in different types of organs and is closely associated with human health. The endometrial receptivity is one of the most important factors in the embryo implantation and development. However, the regulatory mechanism of Zn in endometrium tissue is still unclear. In the study, we found that plasma Zn level is significantly associated with female infertility, which is severely affecting female reproductive health. Primary endometrial stromal cells were isolated from female endometrium and cultured in laboratory. Zn chelator TPEN treatment reduced the expression of stem cell markers CD73, CD90 and CD105 and generated ROS in endometrial stromal cells. However, pre-treatment of Zn (zinc sulfate) is able to prevent TPEN-induced oxidative stress in vitro. By transcriptional profiling and GO analysis, we found that Zn increased the cellular pluripotency signaling and ECM-receptor interaction, but reduced the autophagy, endocytosis and nitrogen metabolism pathway. We further discovered the antioxidant function of Zn through PGC-1α/Nrf2 signaling pathway in the endometrial stromal cells. Zn-supplementation may open up an effective therapeutic approach for patients with oxidative stress-related endometrial diseases.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death worldwide, primarily due to its rapid progression. The current treatment options for PDAC are limited, and a better understanding of the underlying mechanisms responsible for PDAC progression is required to identify improved therapeutic strategies. In this study, we identified FBXO32 as an oncogenic driver in PDAC. FBXO32 was aberrantly upregulated in PDAC, and high FBXO32 expression was significantly associated with an unfavorable prognosis in patients with PDAC. FRG1 deficiency promoted FBXO32 upregulation in PDAC. FBXO32 promoted cell migration and invasion in vitro and tumor growth and metastasis in vivo. Mechanistically, FBXO32 directly interacted with eEF1A1 and promoted its polyubiquitination at the K273 site, leading to enhanced activity of eEF1A1 and increased protein synthesis in PDAC cells. Moreover, FBXO32-catalyzed eEF1A1 ubiquitination boosted the translation of ITGB5 mRNA and activated focal adhesion kinase (FAK) signaling, thereby facilitating focal adhesion assembly and driving PDAC progression. Importantly, interfering with the FBXO32–eEF1A1 axis or pharmaceutical inhibition of FAK by defactinib, an FDA-approved FAK inhibitor, substantially inhibited PDAC growth and metastasis driven by aberrantly activated FBXO32–eEF1A1 signaling. Overall, this study uncovers a mechanism by which PDAC cells rely on FBXO32-mediated eEF1A1 activation to drive progression and metastasis. FBXO32 may serve as a promising biomarker for selecting eligible patients with PDAC for treatment with defactinib. Significance: FBXO32 upregulation in pancreatic cancer induced by FRG1 deficiency increases eEF1A1 activity to promote ITGB5 translation and stimulate FAK signaling, driving cancer progression and sensitizing tumors to the FAK inhibitor defactinib.

The epidermal growth factor receptor (EGFR) family member erb-b2 receptor tyrosine kinase 2 (ERBB2) is overexpressed in many types of cancers leading to (radio- and chemotherapy) treatment resistance, whereas the underlying mechanisms are still unclear. Autophagy is known to contribute to cancer treatment resistance. In this study, we demonstrate that ERBB2 increases the expression of different autophagy genes including ATG12 (autophagy-related 12) and promotes ATG12-dependent autophagy. We clarify that lapatinib, a dual inhibitor for EGFR and ERBB2, promoted autophagy in cells expressing only EGFR but inhibited autophagy in cells expressing only ERBB2. Furthermore, breast cancer database analysis of 35 genes in the canonical autophagy pathway shows that the upregulation of ATG12 and MAP1LC3B is associated with a low relapse-free survival probability of patients with ERBB2-positive breast tumors following treatments. Downregulation of ERBB2 or ATG12 increased cell death induced by chemotherapy drugs in ERBB2-positive breast cancer cells, whereas upregulation of ERBB2 or ATG12 decreased the cell death in ERBB2-negative breast cancer cells. Finally, ERBB2 antibody treatment led to reduced expression of ATG12 and autophagy inhibition increasing drug or starvation-induced cell death in ERBB2-positive breast cancer cells. Taken together, this study provides a novel approach for the treatment of ERBB2-positive breast cancer by targeting ATG12-dependent autophagy.

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Liver cancer is a disease with high mortality; it is often diagnosed at intermediate and advanced stages and has a high recurrence rate. ROS restriction and adequate energy supply play significant roles in liver cancer. SLC25A11, a member of the malate-aspartate shuttle (MAS), regulates electroneutral exchange between 2-oxoglutarate and other dicarboxylates. It transports glutathione (GSH) from the cytoplasm into mitochondria to maintain GSH levels to limit ROS production. Moreover, SLC25A11 is essential for ATP generation in cancers as it regulates NADH transportation from the cytoplasm to mitochondria. The purpose of this research was to investigate the prognostic value of SLC25A11 in liver cancer. The Cancer Genome Atlas database was used to analyze the levels of SLC25A11 in liver cancer. Fisher’s exact and chi-square tests were used to evaluate the relationship between SLC25A11 expression and clinical characteristics. Finally, we explored the value of SLC25A11 in prognosis by Cox analysis and Kaplan-Meier curves. Our results revealed that SLC25A11 was downregulated in liver cancer compared to normal controls. Low expression of SLC25A11 was associated with clinical stage, vital status, histologic grade, overall survival (OS) and relapse-free survival (RFS). Liver cancer patients with low SLC25A11 expression had shorter OS and RFS than patients with high SLC25A11 expression. Multivariate analysis showed that the expression of SLC25A11 was an independent predictor of RFS and OS. In conclusion, this study identified that SLC25A11 serves as a new prognostic marker for liver cancer.