Aims and hypothesis: Epidermal growth factor (EGF) has been shown to induce the migration of various cancer cells. However, the underlying signaling mechanisms for EGFinduced migration of oral squamous cell carcinoma (OSCC) remain to be elucidated. WNT7A, a member of the family of 19 Wnt secreted glycoproteins, is commonly associated with tumor development. It is mostly unknown whether and, if so, how EGF modulates WNT7A in OSCC cells. The role of WNT7A in OSCC was thus investigated to explore the underlying signaling mechanisms for EGF-induced migration of OSCC.Methods: Cell migration was measured by Wound healing assay and Transwell assay. Western blotting was carried out to detect the expression of WNT7A, MMP9, b-catenin, p-AKT, and p-ERK. The cells were transfected with plasmids or siRNA to upregulate or downregulate the expression of WNT7A. The location of b-catenin was displayed by immunofluorescence microscopy. Immunohistochemistry was carried out to confirm the relation between WNT7A expression and OSCC progression.Results: The present study showed that the levels of WNT7A mRNA and protein were increased by EGF stimulation in OSCC cells. Besides, it was proved that p-AKT, but not p-ERK, mediated the expression of WNT7A protein induced by EGF. Furthermore, the inhibition of AKT activation prevented the EGF-induced increase of WNT7A and matrix metallopeptidase 9 (MMP9) expression and translocation of b-catenin from the cytoplasm to the nucleus. Moreover, histological analysis of OSCC specimens revealed an association between WNT7A expression and poor clinical prognosis of the disease. Conclusions:The data in this paper indicated that WNT7A could be a potential oncogene in OSCC and identified a novel PI3K/AKT/WNT7A/b-catenin/MMP9 signaling for EGF-induced migration of OSCC cells.

Tumor cell migration is a critical step in cancer metastasis. Over-activated Notch pathway can promote the migration of cancer cells, especially in the breast cancer. However, the underlying mechanism of non-canonical Notch signaling in modulating the migration has not yet been clearly characterized. Here we demonstrated that DAPT, a gamma secretase inhibitor, inhibited protrusion formation and cell motility, and then reduced the migration of triple-negative breast cancer cells, through increasing the activity of Cdc42 by non-canonical Notch pathway. Phosphorylation of AKT on S473 was surprisingly increased when Notch signaling was inhibited by DAPT. Inhibition of PI3K and AKT by LY294002 and MK2206, respectively, or knockdown of AKT expression by siRNA blocked DAPT-induced activation of Cdc42. Moreover, immunofluorescence staining further showed that DAPT treatment reduced the formation of lamellipodia and induced actin cytoskeleton remodeling. Taken together, these results indicated that DAPT inhibited Notch signaling and consequently activated PI3K/AKT/Cdc42 signaling by non-canonical pathway, facilitated the formation of filopodia and inhibited the assembly of lamellipodia, and finally resulted in the decrease of migration activity of breast cancer cells.

Overactivation of androgen receptor (AR)-mediated signal has been extensively implicated in prostate cancer (CaP) development, progression, and recurrence, which makes it an attractive therapeutic target. Meanwhile, as an endogenous inhibitor of histone deacetylase 1 (HDAC 1), tumor-suppressive mammary serine protease inhibitor (maspin) was reported to sensitize drug-induced apoptosis with a better therapeutic outcome in CaP, but the relationship between AR and maspin remains unclear. In the current study, treatment of 5-Aza or MS-275/enzalutamide induced poly (ADP-ribose) polymerase (PARP) cleavage and p-H2A.X in CaP cells with an increase of maspin expression but a decrease of AR. Then, treatment with protease inhibitor MG132 did not rescue the above drug-induced loss of AR. In addition, modulation of maspin expression by gene recombinant or siRNA technology showed an inverse correlation between expression of maspin and AR, consequently affecting the AR-regulated downstream gene transcription (e.g., NKX3.1 and TMPRSS2). Bioinformatics analysis of the data extracted from the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) database also revealed an inverse correlation between low maspin expression and high AR level in advanced CaP. Furthermore, chromatin immunoprecipitation (ChIP) assay using anti-maspin antibody identified that a portion of AR promoter sequence was co-precipitated and presented in the immunoprecipitated complex. Finally, maspin-mediated repression of AR was induced by treatment of MS-275, which promoted enzalutamide treatment efficacy with decrease of prostate-specific antigen (PSA) expression in LNCaP and 22RV1 cells. Taken together, the data not only demonstrated maspin-mediated repression of AR to augment drug anti-tumor activity but also provided in-depth support for combination of HDAC inhibitors with AR antagonist in CaP therapy.

Gastric cancer (GC) is a global health issue with a high mortality rate. Early diagnosis and tracking of GC is a challenge due to a lack of reliable tools. Amphiregulin (AREG) is a member of the epidermal growth factor (EGF) family that activates growth signaling upon binding of EGF receptors. Elevated AREG expression is associated with various pathological conditions, including cancer. Here, we investigated whether increased AREG expression is a disease indicator and/or prognostic biomarker for GC. We used tissue microarray and quantitative real-time polymerase chain reaction to assess AREG expression in clinical tissue specimens at various stages of GC and a conducted bioinformatics analysis to evaluate the value of AREG over-expression as a GC biomarker. We found that both mRNA and protein expression of AREG were increased in the tissues of GC patients when compared to tissues from non-cancer patients or normal tissues. High expression of AREG was also associated with GC clinicopathological characteristics and poor survival. Thus, over-expression of AREG could serve as a novel GC biomarker, and active surveillance of its expression could be a novel approach to GC diagnosis and monitoring.

Negative-pressure wound therapy (NPWT) is one of the most advanced therapeutic methods in the treatment of various hard-to-heal acute and refractory chronic wounds. Recent emerging evidence points to a role of the microRNA-mediated regulation of angiogenesis in ischemic tissues, and a series of microRNAs associated with angiogenesis have been successively identified. In this study, we found that miR-195 expression was significantly upregulated and the microvessel density (MVD) was increased in granulation tissue collected 7 days after NPWT compared with those in the pre-NPWT tissue. Moreover, the expression of NLRX1, the potential target gene of miR-195, was down-regulated in post-NPWT compared with that in pre-NPWT tissue. Significant negative correlations were detected between miR-195 and NLRX1 expression levels ( r = -.856, P < .001) and between NLRX1 expression and MVD ( r = -.618, P < .05), whereas miR-195 expression was positively correlated with MVD in the granulation tissue ( r = .630, P < .05). In summary, NPWT may suppress NLRX1 expression through the upregulation of miR-195 expression, thus efficaciously promoting angiogenesis in the granulation tissue to enhance wound healing.