Antiapoptotic and Prometastatic Roles of Cytokine FAM3B in Triple-Negative Breast Cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. FAM3B, a secreted protein, has been extensively studied in various types of tumors. However, its function in breast cancer remains poorly understood. METHODS: We analyzed FAM3B expression data from breast cancer patients available at TCGA database and overall survival was analyzed by using the Kaplan-Meier plotter. MDA-MB-231 TNBC tumor cell line and hormone-responsive MCF-7 cell lines were transfected to overexpress FAM3B. We assessed cell death, tumorigenicity, and invasiveness in vitro through MTT analysis, flow cytometry assays, anchorage-independent tumor growth, and wound healing assays, respectively. We performed in vivo evaluation by tumor xenograft in nude mice. RESULTS: In silico analysis revealed that FAM3B expression was lower in all breast tumors. However, TNBC patients with high FAM3B expression had a poor prognosis. FAM3B overexpression protected MDA-MB-231 cells from cell death, with increased expression of Bcl-2 and Bcl-xL, and reduced caspase-3 activity. MDA-MB-231 cells overexpressing FAM3B also exhibited increased tumorigenicity and migration rates in vitro, displaying increased tumor growth and reduced survival rates in xenotransplanted nude mice. This phenotype is accompanied by the upregulation of EMT-related genes Slug, Snail, TGFBR2, vimentin, N-cadherin, MMP-2, MMP-9, and MMP-14. However, these effects were not observed in the MCF-7 cells overexpressing FAM3B. CONCLUSION: FAM3B overexpression contributes to tumor growth, promotion of metastasis, and, consequently, leads to a poor prognosis in the most aggressive forms of breast cancer. Future clinical research is necessary to validate FAM3B as both a diagnostic and a therapeutic strategy for TNBC.

Differential effect of chronic mild stress on anxiety and depressive-like behaviors in three strains of male and female laboratory mice.

Major depressive disorder is the most common psychiatric disorder worldwide. To understand mechanisms and search for new approaches to treating depression, animal models are crucial. Chronic mild stress (CMS) is the most used animal model of depression. Although CMS is considered a robust model of depression, conflicting results have been reported for emotion-related behaviors, which the intrinsic characteristics of each rodent strain could explain. To further shed light on the impact of genetic background on the relevant parameters commonly addressed in depression, we examined the effect of 4-weeks CMS on anxiety and depression-related behaviors and body weight gain in three strain mice (BALB/c, C57BL/6, and CD1) of both sexes. CMS reduced body weight gain in C57BL/6NCrl and CD1 male mice. C57BL/6 animals exhibited a more pronounced anxious-like behavior than CD1 and BALB/c mice in the light-dark box (LDB) and the elevated plus maze (EPM) tests, whereas BALB/c animals exhibited the more robust depressive-like phenotype in the splash test (ST), tail suspension test (TST) and forced-swimming test (FST). Under CMS, exposure did not affect anxiety-related behaviors in any strain but induced depression-like behaviors strain-dependently. CMS C57BL/6 and CD1 mice of both sexes showed depression-like behaviors, and CMS BALB/c male mice exhibited reduced depressive behaviors in the FST. These results suggest a differential effect of stress, with the C57BL/6 strain being more vulnerable to stress than the CD1 and BALB/c strain mice. Furthermore, our findings emphasize the need for researchers to consider mouse strains and behavioral tests in their CMS experimental designs.

WRN modulates translation by influencing nuclear mRNA export in HeLa cancer cells.

BACKGROUND: The Werner syndrome protein (WRN) belongs to the RecQ family of helicases and its loss of function results in the premature aging disease Werner syndrome (WS). We previously demonstrated that an early cellular change induced by WRN depletion is a posttranscriptional decrease in the levels of enzymes involved in metabolic pathways that control macromolecular synthesis and protect from oxidative stress. This metabolic shift is tolerated by normal cells but causes mitochondria dysfunction and acute oxidative stress in rapidly growing cancer cells, thereby suppressing their proliferation. RESULTS: To identify the mechanism underlying this metabolic shift, we examined global protein synthesis and mRNA nucleocytoplasmic distribution after WRN knockdown. We determined that WRN depletion in HeLa cells attenuates global protein synthesis without affecting the level of key components of the mRNA export machinery. We further observed that WRN depletion affects the nuclear export of mRNAs and demonstrated that WRN interacts with mRNA and the Nuclear RNA Export Factor 1 (NXF1). CONCLUSIONS: Our findings suggest that WRN influences the export of mRNAs from the nucleus through its interaction with the NXF1 export receptor thereby affecting cellular proteostasis. In summary, we identified a new partner and a novel function of WRN, which is especially important for the proliferation of cancer cells.