TC2N inhibits distant metastasis and stemness of breast cancer via blocking fatty acid synthesis.

BACKGROUND: Tandem C2 domains, nuclear (TC2N) is a C2 domain-containing protein that belongs to the carboxyl-terminal type (C-type) tandem C2 protein family, and acts as an oncogenic driver in several cancers. Previously, we preliminarily reported that TC2N mediates the PI3K-Akt signaling pathway to inhibit tumor growth of breast cancer (BC) cells. Beyond that, its precise biological functions and detailed molecular mechanisms in BC development and progression are not fully understood. METHODS: Tumor tissues of 212 BC patients were subjected to tissue microarray and further assessed the associations of TC2N expression with pathological parameters and FASN expression. The protein levels of TC2N and FASN in cell lines and tumor specimens were monitored by qRT-PCR, WB, immunofluorescence and immunohistochemistry. In vitro cell assays, in vivo nude mice model was used to assess the effect of TC2N ectopic expression on tumor metastasis and stemness of breast cancer cells. The downstream signaling pathway or target molecule of TC2N was mined using a combination of transcriptomics, proteomics and lipidomics, and the underlying mechanism was explored by WB and co-IP assays. RESULTS: Here, we found that the expression of TC2N remarkedly silenced in metastatic and poorly differentiated tumors. Function-wide, TC2N strongly inhibits tumor metastasis and stem-like properties of BC via inhibition of fatty acid synthesis. Mechanism-wise, TC2N blocks neddylated PTEN-mediated FASN stabilization by a dual mechanism. The C2B domain is crucial for nuclear localization of TC2N, further consolidating the TRIM21-mediated ubiquitylation and degradation of FASN by competing with neddylated PTEN for binding to FASN in nucleus. On the other hand, cytoplasmic TC2N interacts with import proteins, thereby restraining nuclear import of PTEN to decrease neddylated PTEN level. CONCLUSIONS: Altogether, we demonstrate a previously unidentified role and mechanism of TC2N in regulation of lipid metabolism and PTEN neddylation, providing a potential therapeutic target for anti-cancer.

Effects of electroacupuncture combined with paliperidone palmitate long-acting injection on withdrawal symptoms and neurotransmitters in methamphetamine addicts.

OBJECTIVE: To investigate the effects of electroacupuncture combined with paliperidone palmitate long-acting injection (PP-LAI) on withdrawal symptoms and neurotransmitters in methamphetamine (MA) addicts. MATERIALS AND METHODS: A total of 109 methamphetamine addicts, who were treated in the hospital from October 2021 to October 2022, were selected. According to the random number table, the patients were divided into the study group (n=54) and the control group (n=55), in which the control group was treated with PP-LAI and the study group was treated with electroacupuncture on the basis of the control group; the methamphetamine withdrawal symptom score scale was used to assess the therapeutic effect before treatment and within 12 months after treatment; the changes of brain neurotransmitters dopamine, γ-aminobutyric acid, serotonin, acetylcholine values were compared between the two groups. RESULTS: 1) There was no statistical difference in MA withdrawal symptom scores between the two groups before treatment (p>0.05); 2) MA withdrawal symptom scores have a statistically significant difference between the study group and the control group after 3 and 6 months of treatment; 3) dopamine levels in the study group were significantly higher than those in the control group after 6 months of completion of treatment, and γ-aminobutyric acid values and 5- serotonin values in the study group were significantly lower than those in the control group (p<0.05). CONCLUSIONS: Electroacupuncture combined with PP-LAI can partially improve the withdrawal symptoms and anxiety of methamphetamine addicts. This is a potential treatment for preventing relapse of withdrawal symptoms.