Non-alcoholic fatty liver disease
(NAFLD) is a metabolic stress liver injury that is closely related
to obesity, insulin resistance, type 2 diabetes, atherosclerosis,
and metabolic syndrome. The pathological features are diffuse hepatic
vesicular steatosis, including non-alcoholic steatohepatitis, liver
fibrosis, and even liver cancer. A variety of pathological outcomes
cause serious harm to human health. At present, an increasing number
of researchers are investigating the pathogenesis of NAFLD from the
perspective of changes in the function of the intestinal barrier.
The physical, chemical, immunological, and microbiological barriers
in the intestinal tract constitute the complete intestinal barrier,
which plays an important defensive role against the invasion of harmful
substances from the intestines. Protecting the function of the intestinal
barrier is a new way to treat NAFLD and its related diseases. In this
perspective, we summarized the current knowledge of the role of the
intestinal barrier in NAFLD.
Loss of WW domain-containing oxidoreductase (Wwox) expression has been observed in breast cancer (BC). However, its regulatory effects are largely unknown, especially in triple-negative breast cancer (TNBC). Herein, gene expression profiling revealed that JAK/STAT3 pathway was one of the most differentially modulated pathways in basal-like BC cells. The lower expression of Wwox was significantly correlated with high activation of STAT3 in basal-like cells and TNBC tissues. Overexpression of Wwox markedly inhibited proliferation and metastasis of BC cells by suppressing STAT3 activation, which is to interact with JAK2 to inhibit JAK2 and STAT3 phosphorylation. Furthermore, Wwox limited STAT3 binding to the interleukin-6 promoter, repressing expression of the IL-6 cytokine. Altogether, our data established that Wwox suppresses BC cell metastasis and proliferation by JAK2/STAT3 pathway. Targeting of Wwox with STAT3 could offer a promising therapeutic strategy for TNBC.
Pancreatic cancer (PC) is a particularly lethal form of cancer with high potential for metastasis to distant organs. Disruption of cell polarity is a hallmark of advanced epithelial tumours. Here we show that the polarity protein AF6 (afadin and MLLT4) is expressed at low levels in PC. We demonstrate that depletion of AF6 markedly promotes proliferation and metastasis of PC cells through upregulation of the expression of Snail protein, and this requires the nuclear localization of AF6. Furthermore, AF6 deficiency in PC cells leads to increased formation of a Dishevelled 2 (Dvl2)-FOXE1 complex on the promoter region of Snail gene, and activation of Snail expression. Altogether, our data established AF6 as a potential inhibitor of metastasis in PC cells. Targeting the Dvl2-FOXE1-Snail signalling axis may thus represent a promising therapeutic strategy.
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