TC2N Promotes Cell Proliferation and Metastasis in Hepatocellular Carcinoma by Targeting the Wnt/ß-Catenin Signaling Pathway.

Hepatocellular carcinoma (HCC), one of the most prevalent types of cancer worldwide, has an exceedingly poor prognosis. Tandem C2 domain nuclear protein (TC2N) has been implicated in tumorigenesis and serves as an oncogene or tumor suppressor in different types of cancer. Here, we explore the possible regulatory activities and molecular mechanisms of TC2N in HCC progression. However, TC2N expression was significantly upregulated in HCC tissues and hepatoma cell lines, and this upregulation was positively correlated with tumor progression in HCC patients. The ectopic overexpression of TC2N accelerated the proliferation, migration, and invasion of HCC cells, whereas its knockdown showed the opposite effects. Bioinformatics analysis showed that TC2N participates in the regulation of the Wnt/ß-catenin signaling pathway. Mechanistically, TC2N activated the Wnt/ß-catenin signaling pathway by regulating the expression levels of ß-catenin and its downstream targets CyclinD1, MMP7, c-Myc, c-Jun, AXIN2, and glutamine synthase. Furthermore, the deletion of ß-catenin effectively neutralized the regulation of TC2N in HCC proliferation and metastasis. Overall, this study showed that TC2N promotes HCC proliferation and metastasis by activating the Wnt/ß-catenin signaling pathway, indicating that TC2N might be a potential molecular target for the treatment of HCC.

The Olfactory Receptor Olfr25 Mediates Sperm Dysfunction Induced by Low-Dose Bisphenol A through the CatSper-Ca2+ Signaling Pathway.

Bisphenol A (BPA), a typical endocrine disruptor, is known to have various adverse effects on the male reproductive system. However, the toxic effects and mechanisms of low-dose BPA have not yet been fully explored. In this study, male Kunming mice were orally administered low-dose BPA (0.03, 0.3 and 3 mg/kg/d) for ten consecutive weeks. Pathological sections of testicular tissue showed no significant morphological differences after BPA exposure. An analysis of the functional parameters of sperm revealed that exposure to low-dose BPA significantly decreased sperm motility, chemotaxis, and the acrosome reaction. An in vitro BPA exposure model combined with an omics data analysis showed that the olfactory receptor-related pathway was significantly enriched after BPA treatment. Subsequent experiments verified the reduced mRNA level of a novel olfactory receptor gene, Olfr25, in vivo and in vitro exposure models. Meanwhile, exposure to low-dose BPA reduced the intracellular calcium ion concentration and the mRNA levels of pore-forming subunits of the CatSper channel in sperm. Importantly, the knockdown of Olfr25 inhibited calcium ion levels and CatSper subunit expression in GC-2 cells. Olfr25 overexpression attenuated the BPA-induced downregulation of CatSper subunit expression in GC-2 cells. These findings indicate that Olfr25 might participate in low-dose BPA-induced sperm dysfunction by affecting the CatSper-Ca2+ signaling pathway. This study reveals a new mechanism underlying the effects of low-dose BPA on sperm function and provides a reference for assessing the safety of low-dose BPA exposure.

Microplastics cause reproductive toxicity in male mice through inducing apoptosis of spermatogenic cells via p53 signaling.

BACKGROUND: Studies on male reproductive toxicity of microplastics are still scarce and the precise mechanism is not distinct. METHODS: C57BL/6 male mice were given oral gavage treatments treated with 5 µm (MPs) and 80 nm (NPs) polystyrene microplastics every day for 60 consecutive days in a row at dosages of 0, 10 and 40 mg/kg/d. The major damage of MPs and NPs were assessed by the assays in vivo and in vitro. Transcriptome sequencing was applied to screen the key involved pathways. RESULTS: In the 10 mg/kg/d NPs group, there was an increase in testicular organ coefficient, and in the 40 mg/kg/d MPs group, an increase in epididymal weight was observed. Vacuolization of spermatogenic cell layer, interstitial congestion, and germ cell apoptosis were found in the testes of MPs and NPs treatment mice at different dose groups. Higher apoptosis rate was observed in GC-2 cells after MPs and NPs treatment at different concentrations. Transcriptome analysis suggested that p53 pathway might be the key signal pathway of the cell apoptosis, and the expressions of p53 and other markers of cell apoptosis were indeed altered after exposure to MPs and NPs. CONCLUSIONS: MPs and NPs can cause reproductive toxicity in male mice through inducing apoptosis of spermatogenic cells via p53 signaling pathway, indicating MPs and NPs exposure be an unnegligible risk factor for reproductive health in male mice.