TNFAIP3 promotes ALDH-positive breast cancer stem cells through FGFR1/MEK/ERK pathway.

Breast cancer stem cells (BCSCs) are a tiny population of self-renewing cells that may contribute to cancer initiation, progression, and resistance to therapy in patients. In our prior study, we found that tumor necrosis factor alpha-induced protein 3 (TNFAIP3) is necessary for fibroblast growth factors receptor 1 (FGFR1) signaling-promoted tumor growth and progression in breast cancer (BC). This study aims to investigate the involvement of TNFAIP3 in regulating BCSCs. In this work, we showed that ALDH-positive BCSCs were increased by activating the FGFR1-MEK-ERK pathway, meanwhile utilizing FGFR1 inhibitor, MEK inhibitor, or ERK inhibitor reversed the phenomenon in BC cells. Moreover, ALDH-positive BCSCs were decreased in TNFAIP3-knockout or TNFAIP3-depressing cells. In vivo analysis displayed that TNFAIP3-silenced MDA-MB-231 xenografts developed smaller tumors and ALDH immunostaining levels were significantly lower in TNFAIP3-depressing or TNFAIP3-knockout tumor tissues. Besides, our results also revealed that TNFAIP3 influences the transcription stemness factors gene expression. Taken together, TNFAIP3 could be a potential regulator in FGFR1-MEK-ERK-promoted ALDH-positive BCSCs.

TNFAIP3 is required for FGFR1 activation-promoted proliferation and tumorigenesis of premalignant DCIS.COM human mammary epithelial cells.

BACKGROUND: Although ductal carcinoma in situ (DCIS) is a non-invasive breast cancer, many DCIS lesions may progress to invasive cancer and the genes and pathways responsible for its progression are largely unknown. FGFR1 plays an important role in cell proliferation, differentiation and carcinogenesis. The purpose of this study is to examine the roles of FGFR1 signaling in gene expression, cell proliferation, tumor growth and progression in a non-invasive DCIS model. METHODS: DCIS.COM cells were transfected with an empty vector to generate DCIS-Ctrl cells. DCIS-iFGFR1 cells were transfected with an AP20187-inducible iFGFR1 vector to generate DCIS-iFGFR1 cells. iFGFR1 consists of the v-Src myristoylation membrane-targeting sequence, FGFR1 cytoplasmic domain and the AP20187-inducible FKBP12 dimerization domain, which simulates FGFR1 signaling. The CRISPR/Cas9 system was employed to knockout ERK1, ERK2 or TNFAIP3 in DCIS-iFGFR1 cells. Established cell lines were treated with/without AP20187 and with/without FGFR1, MEK, or ERK1/2 inhibitor. The effects of these treatments were determined by Western blot, RNA-Seq, real-time RT-PCR, cell proliferation, mammosphere growth, xenograft tumor growth, and tumor histopathological assays. RESULTS: Activation of iFGFR1 signaling in DCIS-iFGFR1 cells enhanced ERK1/2 activities, induced partial epithelial-to-mesenchymal transition (EMT) and increased cell proliferation. Activation of iFGFR1 signaling promoted DCIS growth and progression to invasive cancer derived from DCIS-iFGFR1 cells in mice. Activation of iFGFR1 signaling also altered expression levels of 946 genes involved in cell proliferation, migration, cancer pathways, and other molecular and cellular functions. TNFAIP3, a ubiquitin-editing enzyme, is upregulated by iFGFR1 signaling in a FGFR1 kinase activity and in an ERK2-dependent manner. Importantly, TNFAIP3 knockout not only inhibited the AP20187-induced proliferation and tumor growth of DCIS-iFGFR1 cells, but also further reduced baseline proliferation and tumor growth of DCIS-iFGFR1 cells without AP20187 treatment. CONCLUSIONS: Activation of iFGFR1 promotes ERK1/2 activity, EMT, cell proliferation, tumor growth, DCIS progression to invasive cancer, and altered the gene expression profile of DCIS-iFGFR1 cells. Activation of iFGFR1 upregulated TNFAIP3 in an ERK2-dependent manner and TNFAIP3 is required for iFGFR1 activation-promoted DCIS.COM cell proliferation, mammosphere growth, tumor growth and progression. These results suggest that TNFAIP3 may be a potential target for inhibiting DCIS growth and progression promoted by FGFR1 signaling.

Noise monitoring and adverse health effects in residents in different functional areas of Luzhou, China.

The purpose of the study was to investigate the noise pollution situation and the resulting adverse effect on residents' health in Luzhou, China, to provide data for noise pollution prevention policies and interventions. Four different functional areas (commercial, construction, residential, and transportation hub areas) were chosen to monitor noise level for 3 months. The survey was performed by questionnaire on the spot on randomly selected individuals; it collected data on the impact of noise on residents' health (quality of sleep, high blood pressure, subjective feeling of nervous system damage, and attention) as well as the knowledge of noise-induced health damage, the degree of adaptation to noise, and their solutions. The noise levels of residential, commercial, transportation, and construction areas exceeded the national standards (P < .001). Sleep quality, prevalence of hypertension, and attention in transportation hub areas were significantly different from those in the other 3 areas (P < .05); only 24.46% of people knew the health hazards associated with noise; 64.57% of residents have adapted to the current noise environment. Most of them have to close the doors and windows to reduce noise. The noise pollution situation in Luzhou, China, is serious, especially the traffic noise pollution. Residents pay less attention to it and adopt single measures to reduce the noise. We should work toward the prevention and control of traffic noise and improve the residents' awareness to reduce the adverse health effects of noise.