It is one of the important events that trophoblast cells within the placental folds differentiate into two types that differ in cell shape during placental development in pigs. This study showed that all the trophoblast cells were of similar shape between Yorkshire and Chinese Meishan pigs on day 26 of gestation; thereafter, the trophoblast cells located at the top of the placental folds became high columnar, while those cells at the base of the placental folds were cuboidal on day 50 of gestation. Additionally, on day 95 of gestation, all the trophoblast cells in Meishan pigs became cuboidal, but the trophoblast cells located at the top of the placental folds in Yorkshire pigs still remained columnar. The membranous E-cadherin and β-catenin were strongly co-expressed by the high columnar trophoblast cells but very weakly expressed by those cuboidal cells. Consistently, the expression pattern of ZEB2, the E-cadherin repressor, was inversely correlated with that of E-cadherin in the two types of trophoblast cells in the two breeds. Furthermore, electrophoretic mobility shift assays demonstrated the binding of ZEB2 to the E-cadherin promoter in nuclear extracts from porcine placental tissue. These findings suggest a ZEB2-dependent mechanism of trophoblast cell differentiation during placental development in pigs.

Hepatitis B virus (HBV) infection is one of main contributors to poor prognosis and rapid progression of hepatocellular cancer (HCC). We previously identified the important role of the phosphorylation of ubiquitin-like with PHD and ring finger domains (UHRF2) in HBV-associated HCC. In this study we identify upregulated UHRF2 protein levels in HBV-associated HCC cells and tissues. UHRF2 overexpression promotes the viability, proliferation, migration and invasiveness of HBV-positive HCC cell lines, and enhances HBV DNA replication. To obtain a comprehensive understanding of the interaction networks of UHRF2 and their underlying mechanism, this study suggests that UHRF2 facilitates the ubiquitin-proteasome-mediated proteolysis of DExD/H (Asp-Glu-Ala-His) -box helicase enzyme 9 (DHX9). However, phosphorylation of UHRF2 by HBx at S643 inhibits E3 ubiquitin ligase activity of UHRF2 and improves DHX9 protein stability. Furthermore, results suggest that HBx promotes phosphorylation of UHRF2 by the ETS1-CDK2 axis through the downregulation of miR-222-3p in HBV-associated HCC specimens and cells. Our findings suggest that HBx-induced phosphorylation of UHRF2 S643 acts as a “switch” in HBV-associated HCC oncogenesis, activating the positive feedback between phosphorylated UHRF2 and HBV, provide evidence that UHRF2 is a new regulator and a potential prognostic indicator of poor prognosis for HBV-associated HCC.

Bevacizumab is an anti-angiogenic agent widely used in neoadjuvant chemotherapy for advanced triple-negative breast cancer (TNBC). TNBC patients frequently acquire resistance to bevacizumab due to the hypoxic tumor microenvironment, yet the underlying molecular mechanism remains unclear. Here, we demonstrate that mitochondrial reprogramming under hypoxia is crucial for resistance to bevacizumab. Mechanically, prolonged hypoxia causes the glycolytic pathway enzyme PDK1 to accumulate inside mitochondria. In mitochondria, PDK1 exerts its non-canonical function to phosphorylate mitochondrial protein Prohibitin 2 (PHB2) at Ser190. Phosphorylation at Ser190 stabilizes PHB2 and enhances its binding with LC3, thereby initiating mitophagy. Functionally, mitochondrial PDK1 (mito-PDK1) initiates mitophagy in response to hypoxia-induced mitochondrial damage and promotes the malignant phenotype of TNBC cells. In xenograft tumors, inhibiting the function of mito-PDK1 enhances the sensitivity to bevacizumab. Collectively, our findings identify the crucial function and mechanism of mito-PDK1 in TNBC. Targeting mito-PDK1 function may emerge as a novel therapeutic strategy to address acquired resistance to bevacizumab.

Tumor suppressor p53 is the most frequently mutated gene in cancers. Mutations in p53 not only result in the loss of its classical tumor‐suppressive functions but also confer new oncogenic properties. The protein stabilization of mutant p53 (mutp53) is a prerequisite for gain‐of‐function manifestation. Here, we report the novel mechanism that pyruvate dehydrogenase kinase1 (PDK1) modulates both wild‐type and mutant p53, and facilitates proliferation and migration of TP53 mutant breast cancer. On the one hand, we identified PDK1 as a direct transcriptional repression target of wild‐type p53, whereas transcriptional activation of PDK1 in mutp53 cells is initiated by the EGR1 axis. On the other hand, PDK1 promoted mutp53 protein accumulation by binding to mutp53 and inhibiting its degradation. Taken together, mutp53 activated a positive feedback loop by upregulating PDK1 to enhance p53 protein stability and promote the malignancy of breast cancer. Moreover, PDK1 inhibition increased the therapeutic effect of APR‐246 on TP53 mutant breast cancer in xenograft tumors. Our results suggested that intervention of PDK1 could potentially emerge as a new therapeutic strategy to impede the progression of TP53 mutant breast cancer.