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In this study, we had developed an organocatalyst-controlled site-selectivity switchable Friedel-Crafts reaction of 1-naphthols and 2,3-dioxopyrrolidines. The o-selective Friedel-Crafts reaction was achieved with chiral tertiary amines while p-selective Friedel-Crafts reaction...

BACKGROUND/AIM Hepatitis B virus-encoded X protein (HBx) plays a pivotal role in hepatocellular carcinoma (HCC) progression and treatment resistance. Interestingly, our previous study unexpectedly showed that full-length HBx sensitized HCC cells to lapatinib by up-regulating erb-b2 receptor tyrosine kinase 3 (ERBB3). We further aimed to map the exact motif within the HBx sequence responsible for lapatinib sensitization. MATERIALS AND METHODS The exact motif responsible for the lapatinib sensitization was assessed by construction of various fragments of HBx. Cell viability was examined by the MTT assay and crystal violet staining. RESULTS Our investigation found that lapatinib sensitivity and up-regulation of ERBB3 promoter activity were observed only in HCC cells expressing C-terminal residues of HBx. Furthermore, C-terminal HBx peptide induced ERBB3 protein expression and sensitivity to lapatinib. CONCLUSION These results not only indicate that the C-terminus of HBx is required for lapatinib sensitivity, but also provide clues to developing a predictive biomarker for response of HCC to lapatinib in the future.

Background/aim Sorafenib is now standard treatment for advanced hepatocellular carcinoma (HCC). However, therapeutic efficacy is not as good as was predicted. Many efforts are being made to improve HCC sensitivity to sorafenib. Our previous study demonstrated that co-treatment with chrysin enhanced sorafenib sensitivity through inhibition of ATP-binding cassette super-family G member 2 (ABCG2). Whether there is another mechanism other than inhibition of ABCG2 underlying chrysin-mediated synergistic effect is still not completely elucidated. Materials and methods Phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) was examined by western blot. Cell viability was examined by crystal violet staining. The importance of ERK1/2 phosphorylation was assessed by overexpression and blockage of mitogen-activated protein kinase kinase 1 (MEK1). Results Chrysin induced sustained ERK1/2 phosphorylation of HCC cells in both time- and dose-dependent manners. Overexpression of MEK1 enhanced, whereas blockage of MEK1 led to loss of chrysin-synergized sorafenib effect, through modulating ERK1/2 phosphorylation level. Conclusion These results identify another novel mechanism underlying chrysin-mediated synergistic effect on sorafenib activity in HCC cells.

Hepatitis B virus-encoded X protein (HBx) plays a pivotal role in hepatocellular carcinoma (HCC) progression and treatment resistance. Interestingly, our previous study unexpectedly showed that full-length HBx sensitized HCC cells to lapatinib by up-regulating erb-b2 receptor tyrosine kinase 3 (ERBB3). We further aimed to map the exact motif within the HBx sequence responsible for lapatinib sensitization.The exact motif responsible for the lapatinib sensitization was assessed by construction of various fragments of HBx. Cell viability was examined by the MTT assay and crystal violet staining.Our investigation found that lapatinib sensitivity and up-regulation of ERBB3 promoter activity were observed only in HCC cells expressing C-terminal residues of HBx. Furthermore, C-terminal HBx peptide induced ERBB3 protein expression and sensitivity to lapatinib.These results not only indicate that the C-terminus of HBx is required for lapatinib sensitivity, but also provide clues to developing a predictive biomarker for response of HCC to lapatinib in the future.

// Wei-Chien Huang 1, 2, 3, 4 , Chao-Ming Hung 5, 6 , Ching-Ting Wei 5, 6, * , Tsung-Ming Chen 7, * , Pei-Hsuan Chien 8 , Hsiao-Lin Pan 5 , Yueh-Ming Lin 9 , Yun-Ju Chen 5, 8, 10 1 The Ph.D. program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung 404, Taiwan 2 Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan 3 Center for Molecular Medicine, China Medical University and Hospital, Taichung 404, Taiwan 4 Department of Biotechnology, Asia University, Taichung 413, Taiwan 5 School of Medicine for International Students, I-Shou University, Kaohsiung 824, Taiwan 6 Department of General Surgery, E-Da Hospital, Kaohsiung 824, Taiwan 7 Department and Graduate Institute of Aquaculture, National Kaohsiung Marine University, Kaohsiung 811, Taiwan 8 Department of Medical Research, E-Da Hospital, Kaohsiung 824, Taiwan 9 Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan 10 Department of Biological Science & Technology, I-Shou University, Kaohsiung 824, Taiwan * These authors have contributed equally to this work Correspondence to: Yun-Ju Chen, email: yjchen0326@isu.edu.tw Keywords: lapatinib, interleukin-6, HER2, resistance, breast cancer Received: February 10, 2016 Accepted: August 09, 2016 Published: August 22, 2016 ABSTRACT Lapatinib is an inhibitor of human epidermal growth factor receptor 2 (HER2), which is overexpressed in 20-25% of breast cancers. Clinically, lapatinib has shown promising benefits for HER2-positive breast cancer patients; however, patients eventually acquire resistance, limiting its long-term use. In a previous study, we found that interleukin-6 (IL-6) production was increased in acquired lapatinib-resistant HER2-positive breast cancer cells. In the present study, we confirmed that lapatinib-resistant cells had elevated IL-6 expression and also maintained both stemness population and property. The increase in IL-6 was required for stemness property maintenance, which was mediated primarily through the activation of signal transducer and activator of transcription 3 (STAT3). Blocking IL-6 activity reduced spheroid formation, cell viability and subsequently overcame lapatinib resistance, whereas stimulation of IL-6 rendered parental cells more resistant to lapatinib-induced cytotoxicity. These results point to a novel mechanism underlying lapatinib resistance and provide a potential strategy to overcome resistance via IL-6 inhibition.

Cyclooxygenase-2 (COX-2) is frequently overexpressed and enhances colorectal cancer (CRC) tumorigenesis, including cancer stem cell (CSC) regulation. Accordingly, nonsteroidal anti-inflammatory drugs (NSAIDs), inhibiting COX-1/2 activity, are viewed as potential drugs for CRC treatment. Accumulated evidence indicates that celecoxib has the most potency for antitumor growth among NSAIDs and the underlying mechanism is only partly dependent on COX-2 inhibition. However, the potency of these NSAIDs on CSC inhibition is still not known. In this study, we found that among these NSAIDs, celecoxib has the most potency for CSC inhibition of CRC cells, largely correlating to inhibition of c-Met, not COX-2. Further analysis reveals that c-Met activity was required for basal CSC property. Silence of c-Met blocked whereas overexpression of c-Met enhanced the celecoxib-inhibited CSC property. Collectively, these results not only first elucidate the mechanism underlying celecoxib-inhibited CSC but also indicate c-Met as a critical factor for the CSC property of CRC cells.

Maspin suppresses tumor progression by promoting cell adhesion and apoptosis and by inhibiting cell motility. However, its role in tumorigenesis of hepatocellular carcinoma (HCC) remains unclear. The gene regulation of maspin and its relationship with HCC patient prognosis were investigated in this study. Maspin expression was specifically reduced in HBV-associated patients and correlated with their poor prognosis. Maspin downregulation in HCC cells was induced by HBx to promote their motility and resistance to anoikis and chemotherapy. HBx-dependent induction of microRNA-7, -107, and -21 was further demonstrated to directly target maspin mRNA, leading to its protein downregulation. Higher expressions of these microRNAs also correlated with maspin downregulation in HBV-associated patients, and were associated with their poor overall survival. These data not only provided new insights into the molecular mechanisms of maspin deficiency by HBx, but also indicated that downregulation of maspin by microRNAs confers HBx-mediated aggressiveness and chemoresistance in HCC.

Butein (3,4,2',4'-tetrahydroxychalcone) is a promising natural polyphenolic compound that shows the growth inhibitory activity in human cancer cells; however, the precise mechanism is still unclear. Securin plays pivotal role in cancer cell proliferation and tumorigenesis. Here, we report the presence of securin that could modulate apoptosis and tumor growth ability in the butein-treated human colorectal cancer. Butein induced caspase-3 activation and PARP protein cleavage for apoptosis induction in human colorectal cancer cells. Interestingly, butein reduced the securin protein levels but conversely increased the phospho-histone H3 proteins, mitotic arrest and abnormal chromosomes segregation in cancer cells. The securin-null colorectal cancer cells were more sensitive on the reduction of cell viability than the securin-wild type cancer cells following butein treatment. The loss of securin in human colorectal cancer cells decreased tumor growth ability in nude mice. Moreover, butein reduced the tumor size of xenografted human colorectal tumors of nude mice. Taken together, this study demonstrates for the first time that the depletion of securin mediates the butein-induced apoptosis and colorectal tumor inhibition.

Introduction Triple-negative breast cancer (TNBC), a subtype of breast cancer with negative expressions of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), is frequently diagnosed in younger women and has poor prognosis for disease-free and overall survival. Due to the lack of known oncogenic drivers for TNBC proliferation, clinical benefit from currently available targeted therapies is limited, and new therapeutic strategies are urgently needed. Methods Triple-negative breast cancer cell lines were treated with proteasome inhibitors in combination with lapatinib (a dual epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor). Their in vitro and in vivo viability was examined by MTT assay, clonogenic analysis, and orthotopic xenograft mice model. Luciferase reporter gene, immunoblot, and RT-qPCR, immunoprecipitation assays were used to investigate the molecular mechanisms of action. Results Our data showed that nuclear factor (NF)-κB activation was elicited by lapatinib, independent of EGFR/HER2 inhibition, in TNBCs. Lapatinib-induced constitutive activation of NF-κB involved Src family kinase (SFK)-dependent p65 and IκBα phosphorylations, and rendered these cells more vulnerable to NF-κB inhibition by p65 small hairpin RNA. Lapatinib but not other EGFR inhibitors synergized the anti-tumor activity of proteasome inhibitors both in vitro and in vivo. Our results suggest that treatment of TNBCs with lapatinib may enhance their oncogene addiction to NF-κB, and thus augment the anti-tumor activity of proteasome inhibitors. Conclusions These findings suggest that combination therapy of a proteasome inhibitor with lapatinib may benefit TNBC patients.

Hepatitis B virus- (HBV-) associated hepatocellular carcinoma (HCC) is the most common type of liver cancer. However, the underlying mechanism of HCC tumorigenesis is very complicated and HBV-encoded X protein (HBx) has been reported to play the most important role in this process. Activation of downstream signal pathways of epidermal growth factor receptor (EGFR) family is known to mediate HBx-dependent HCC tumor progression. Interestingly, HER2 (also known as ErbB2/Neu/EGFR2) is frequently overexpressed in HBx-expressing HCC patients and is associated with their poor prognosis. However, it remains unclear whether and how HBx regulates HER2 expression. In this study, our data showed that HBx expression increased HER2 protein level via enhancing its mRNA stability. The induction of RNA-binding protein HuR expression by HBx mediated the HER2 mRNA stabilization. Finally, the upregulated HER2 expression promoted the migration ability of HBx-expressing HCC cells. These findings deciphered the molecular mechanism of HBx-mediated HER2 upregulation in HBV-associated HCC.

Hepatitis B virus (HBV) infection accounts for over a half of cases of hepatocellular carcinoma (HCC), the most frequent malignant tumor of the liver. HBV-encoded X (HBx) plays critical roles in HBV-associated hepatocarcinogenesis. However, it is unclear whether and how HBx regulates the expression of epidermal growth factor receptor (EGFR), an important gene for cell growth. Therefore, the study aimed to investigate the association between HBx and EGFR expression. In this study, we found that HBx upregulates miR-7 expression to target 3′UTR of EGFR mRNA, which in turn results in the reduction of EGFR protein expression in HCC cells. HBx-mediated EGFR suppression renders HCC cells a slow-growth behavior. Deprivation of HBx or miR-7 expression or restoration of EGFR expression can increase the growth rate of HCC cells. Our data showed the miR-7-dependent EGFR suppression by HBx, supporting an inhibitory role of HBx in the cell growth of HCC. These findings not only identify miR-7 as a novel regulatory target of HBx, but also suggest HBx-miR-7-EGFR as a critical signaling in controlling the growth rate of HCC cells.

The multikinase inhibitor, sorafenib (Nexavar®, BAY43-9006), which inhibits both the Raf/MEK/ERK pathway and several receptor tyrosine kinases (RTKs), has shown significantly therapeutic benefits in advanced hepatocellular carcinoma (HCC). However, not all HCC patients respond to sorafenib well and new therapeutic strategies to optimize the efficacy of sorafenib are urgently required. Overexpression of breast cancer resistance protein (BCRP/ABCG2) mediates the drug-efflux of several tyrosine kinase inhibitors (TKIs) to attenuate their efficacy. This study aimed to investigate the role of BCRP/ABCG2 in the sensitivity of HCC to sorafenib. Our data showed that BCRP/ABCG2 mediated the efflux of sorafenib. Co-treatment with a BCRP/ABCG2 inhibitor greatly augmented the cytotoxicity of sorafenib in HCC cells. Similar results were also achieved by the competitive inhibitor of BCRP/ABCG2, gefitinib, in combination with sorafenib. These results suggest not only that BCRP/ABCG2 is a potential predictor for the sorafenib sensitivity in HCC, but also that blockage of BCRP/ABCG2 may be a potential strategy to increase the response of HCC cells to sorafenib.