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Diphenyl difluoroketone (EF-24), a synthetic curcumin analog, has enhanced bioavailability over curcumin. EF-24 acts more powerful bioactivity for anti-inflammatory and anti-cancer activity. However, the effects and mechanism of EF-24 on cervical cancer has not been fully investigated. Herein, this study evaluated the effects of EF-24 on TPA-induced cellular migration of cervical cancer. The results showed that EF-24 substantially reduced the cellular migration and cellular invasion of the HeLa and SiHa cells. Moreover, gelatin zymography, western blotting analyses and real-time PCR revealed that EF-24 suppressed Matrix metalloproteinase-9 (MMP-9) activity, protein expression and mRNA levels. Mechanistically, EF-24 inhibited the phosphorylation of the p38 signaling pathway. In conclusion, EF-24 inhibited TPA-induced cellular migration and cellular invasion of cervical cancer cell lines through modulating MMP-9 expression via downregulating signaling p38 pathway and EF-24 may have potential to serve as a chemopreventive agent of cervical cancer.

Simple Summary Carbonic anhydrase IX (CAIX) is a hypoxia-induced protein that is highly expressed in numerous human cancers. However, the molecular mechanisms involved in CAIX and human cervical cancer metastasis remain poorly understood. Our study found that CAIX overexpression increases PFKFB4 expression and EMT, promoting cervical cancer cell migration. CAIX could contribute to cervical cancer cell metastasis and its inhibition could be a cervical cancer treatment strategy. Abstract Carbonic anhydrase IX (CAIX) is a hypoxia-induced protein that is highly expressed in numerous human cancers. However, the molecular mechanisms involved in CAIX and human cervical cancer metastasis remain poorly understood. In this study, CAIX overexpression in SiHa cells increased cell migration and epithelial-to-mesenchymal transition (EMT). Silencing CAIX in the Caski cell line decreased the motility of cells and EMT. Furthermore, the RNA-sequencing analysis identified a target gene, bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB4), which is influenced by CAIX overexpression and knockdown. A positive correlation was found between CAIX expression and PFKFB4 levels in the cervical cancer of the TCGA database. Mechanistically, CAIX overexpression activated the phosphorylation of extracellular signal-regulated kinases (ERKs) to induce EMT and promote cell migration. In clinical results, human cervical cancer patients with CAIXhigh/PFKFB4high expression in the late stage had higher rates of lymph node metastasis and the shortest survival time. Our study found that CAIX overexpression increases PFKFB4 expression and EMT, promoting cervical cancer cell migration. CAIX could contribute to cervical cancer cell metastasis and its inhibition could be a cervical cancer treatment strategy.

// Chang-Tai Chen 1, 2, * , Ming-Ju Hsieh 3, 4, 5, * , Yi-Hsien Hsieh 6 , Min-Chieh Hsin 3 , Yi-Ting Chuang 3 , Shun-Fa Yang 3, 7 , Jia-Sin Yang 3, 7 and Chiao-Wen Lin 1, 2, 8 1 Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan 2 School of Dentistry, Chung Shan Medical University, Taichung, Taiwan 3 Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan 4 Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan 5 Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan 6 Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan 7 Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan 8 Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan * These authors contributed equally to this work Correspondence to: Chiao-Wen Lin, email: cwlin@csmu.edu.tw Jia-Sin Yang, email: cshe857@csh.org.tw Keywords: sulforaphane; cathepsin S; LC3; oral cancer; migration Received: November 09, 2017 Accepted: February 28, 2018 Published: April 03, 2018 ABSTRACT Sulforaphane has been demonstrated to exert numerous biological effects, such as neuroprotective, anti-inflammatory, and anticancer effects. However, the detailed effects of sulforaphane on human oral cancer cell migration and the underlying mechanisms remain unclear. In this study, we observed that sulforaphane attenuated SCC-9 and SCC-14 cell motility and invasiveness by reducing cathepsin S expression. Moreover, sulforaphane increased microtubule-associated protein 1 light chain 3 (LC3) conversion, and the knockdown of LC3 by siRNA increased cell migration ability. Regarding the mechanism, sulforaphane inhibited the cell motility of oral cancer cells through the extracellular signal-regulated kinase (ERK) pathway, which in turn reversed cell motility. In conclusion, sulforaphane suppress cathepsin S expression by inducing autophage through ERK signaling pathway. Thus, cathepsin S and LC3 may be new targets for oral cancer treatment.

The purpose of this study was to investigate genetic impact of TIMP-3 -1296 T>C (rs9619311) and TIMP-4 -55 T>C (rs3755724) gene polymorphisms on the susceptibility and clinicopathological characteristics of hepatocellular carcinoma (HCC). A total of 759 subjects, including 530 healthy controls and 229 patients with hepatocellular carcinoma, were recruited in this study. Allelic discrimination of TIMP-3 -1296 T>C (rs9619311) and TIMP-4 -55 T>C (rs3755724) polymorphisms was assessed with the ABI StepOne™ Real-Time PCR System. Among women group, individuals with TC or CC alleles of TIMP-3 -1296 T>C gene polymorphism protected against HCC (AOR = 0.35, 95% confidence interval (CI) = 0.12–0.97; p = 0.04) compared to individuals with TT alleles, after adjusting for other confounders. Also, women with TC alleles and with TC or CC alleles of TIMP-4 -55 T>C polymorphisms had a 2.52-fold risk (95%CI = 1.23–5.13; p = 0.01) and 2.47-fold risk (95%CI = 1.26–4.87; p = 0.008) of developing HCC compared to individuals with TT alleles, after adjusting for other confounders. There was no synergistic effect between gene polymorphism and environmental risk factors, including tobacco and alcohol consumptions and clinical statuses of HCC as well as serum expression of liver-related clinicopathological markers. In conclusion, gene polymorphisms of TIMP-3 -1296 T>C (rs9619311) and TIMP-4 -55 T>C (rs3755724) play a role in the susceptibility of HCC among Taiwan women.

Hispolon, a phenolic compound isolated from Phellinus igniarius, induces apoptosis and anti-tumor effects in cancers. However, the molecular mechanism involved in hispolon-mediated tumor-suppressing activities observed in cervical cancer is poorly characterized. Here, we demonstrated that treatment with hispolon inhibited cell metastasis in two cervical cancer cell lines. In addition, the downregulation of the lysosomal protease Cathepsin S (CTSS) was critical for hispolon-mediated suppression of tumor cell metastasis in both in vitro and in vivo models. Moreover, hispolon induced autophagy, which increased LC3 conversion and acidic vesicular organelle formation. Mechanistically, hispolon inhibited the cell motility of cervical cells through the extracellular signal-regulated kinase (ERK) pathway, and blocking of the ERK pathway reversed autophagy-mediated cell motility and CTSS inhibition. Our results indicate that autophagy is essential for decreasing CTSS activity to inhibit tumor metastasis by hispolon treatment in cervical cancer; this finding provides a new perspective on molecular regulation.