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// Ching-Yuan Wu 1, 2 , Yao-Hsu Yang 1, 2 , Yin-Yin Lin 1 , Feng-Che Kuan 3 , Yu-Shin Lin 4 , Wei-Yu Lin 5, 6 , Ming-Yen Tsai 7 , Jia-Jing Yang 1 , Yu-Ching Cheng 1 , Li-Hsin Shu 1 , Ming-Chu Lu 3 , Yun-Ju Chen 8, 9 , Kuan-Der Lee 2 and Hong-Yo Kang 8, 9 1 Department of Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan 2 School of Chinese medicine, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan 3 Department of Hematology and oncology, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan 4 Department of Pharmacy, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan 5 Department of Urology, Chang Gung Memorial Hospital at Chiayi, Puzi City, Taiwan 6 Chang Gung University of Science and Technology, Chia-Yi, Taiwan 7 Department of Chinese Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung, Taiwan 8 Graduate Institute of Clinical Medical Sciences, Chang Gung University, College of Medicine, Kaohsiung, Taiwan 9 Hormone Research Center, Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan Correspondence to: Kuan-Der Lee, email: kdlee@cgmh.org.tw Hong-Yo Kang, email: hkang3@mail.cgu.edu.tw Keywords: dihydroisotanshinone I, STAT3, prostate cancer, Skp2, CCL2 Received: May 10, 2016 Accepted: January 10, 2017 Published: February 01, 2017 ABSTRACT Danshen (Salvia miltiorrhiza Bunge) is widely used in traditional Chinese medicine. In our study, the in vivo protective effect of danshen in prostate cancer patients was validated through data from the National Health Insurance Research Database in Taiwan. In vitro , we discovered that dihydroisotanshinone I (DT), a bioactive compound present in danshen, can inhibit the migration of both androgen-dependent and androgen-independent prostate cancer cells. In addition, we noted that DT substantially inhibited the migratory ability of prostate cancer cells in both a macrophage-conditioned medium and macrophage/prostate cancer coculture medium. Mechanistically, DT both diminished the ability of prostate cancer cells to recruit macrophages and reduced the secretion of chemokine (C-C motif) ligand 2 (CCL2) from both macrophages and prostate cancer cells in a dose-dependent manner. Moreover, DT inhibited the protein expression of p-STAT3 and decreased the translocation of STAT3 into nuclear chromatin. DT also suppressed the expression of tumor epithelial–mesenchymal transition genes, including RhoA and SNAI1. In conclusion, danshen can prolong the survival rate of prostate cancer patients in Taiwan. Furthermore, DT can inhibit the migration of prostate cancer cells by interrupting the crosstalk between prostate cancer cells and macrophages via the inhibition of the CCL2/STAT3 axis. These results may provide the basis for a new therapeutic approach toward the treatment of prostate cancer progression.

// 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.

Maspin is a tumor suppressor that stimulates apoptosis and inhibits metastasis in various cancer types, including hepatocellular carcinoma (HCC). Our previous study has demonstrated that HBx induced microRNA-7, 103, 107, and 21 expressions to suppress maspin expression, leading to metastasis, chemoresistance, and poor prognosis in HCC patients. However, it remains unclear how HBx elicits these microRNA expressions. HBx has been known to induce aberrant activation and nuclear translocation of inhibitor-κB kinase-α (IKKα) to promote HCC progression. In this study, our data further revealed that nuclear IKKα expression was inversely correlated with maspin expression in HBV-associated patients. Nuclear IKKα but not IKKβ reduced maspin protein and mRNA expression, and inhibition of IKKα reverses HBx-mediated maspin downregulation and chemoresistance. In response to HBx overexpression, nuclear IKKα was further demonstrated to induce the gene expressions of microRNA-7, -103, -107, and -21 by directly targeting their promoters, thereby leading to maspin downregulation. These findings indicated nuclear IKKα as a critical regulator for HBx-mediated microRNA induction and maspin suppression, and suggest IKKα as a promising target to improve the therapeutic outcome of HCC patients.

Although radiation therapy was known to be effective to cervical cancer, loco-regional recurrences are frequently found in patients. We aimed to identify a molecular marker predicting the response of cervical cancer to radiotherapy. We included the patients (n = 149) with cervical cancer who had undergone radiotherapy from 2004 to 2006. Tumor samples were collected to examine the association between the expression of S-phase kinase-associated protein 2 (SKP2) and prognosis in cervical cancer. We found higher expression of SKP2 associated with recurrence (HRs: 2.52, p < 0.001), death (HRs: 2.01, p < 0.001) and higher locoregional recurrence rate (HRs: 3.76, p < 0.001). Cervical cancer cell lines with higher expression of SKP2 showed higher colony formation, cell survival rate and fewer DNA damages after irradiation. SKP2-C25, an inhibitor for SKP2 activity, dose-dependently decreased cell viability after irradiation and knockdown of SKP2 impaired DNA-damage response and sensitized the cervical cancer cells to irradiation. Our data showed the SKP2 represents a promising tool to identify patients with cervical cancer who have a higher risk of locoregional recurrence after radiotherapy. Targeting SKP2 may serve as a potential radiosensitizer for developing effective therapeutic strategies against cervical cancer.

Poor prognosis of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) involves HBV X protein (HBx)-induced tumor progression. HBx also contributes to chemo-resistance via inducing the expressions of anti-apoptosis and multiple drug resistance genes. However, the impact of HBx expression on the therapeutic efficacy of various receptor tyrosine kinase inhibitors remains unknown. In this study, our data showed that HBx overexpression did not alter the cellular sensitivity of HCC cell lines to sorafenib but unexpectedly enhanced the cell death induced by EGFR family inhibitors, including gefitinib, erlotinib, and lapatinib due to ErbB3 up-regulation. Mechanistically, HBx transcriptionally up-regulates ErbB3 expression in a NF-κB dependent manner. In addition, HBx also physically interacts with ErbB2 and ErbB3 proteins and enhances the formation of ErbB2/ErbB3 heterodimeric complex. The cell viability of HBx-overexpressing cells was decreased by silencing ErbB3 expression, further revealing the pivotal role of ErbB3 in HBx-mediated cell survival. Our data suggest that HBx shifts the oncogenic addiction of HCC cells to ErbB2/ErbB3 signaling pathway via inducing ErbB3 expression and thereby enhances their sensitivity to EGFR/ErbB2 inhibitors.

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.

// Yu-Chun Hsiao 1, * , Ming-Hsin Yeh 2, * , Yun-Ju Chen 3, 4 , Ju-Fang Liu 5 , Chih-Hsin Tang 6, 7, 8 , Wei-Chien Huang 1, 8, 9, 10 1 The Ph.D. program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan 2 Department of Surgery, Chung-Shan Medical University Hospital, Taichung, Taiwan 3 Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan 4 Department of Biological Science & Technology, I-Shou University, Kaohsiung, Taiwan 5 Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan 6 Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan 7 Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan 8 Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan 9 Center for Molecular Medicine, China Medical University and Hospital, Taichung, Taiwan 10 Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan * These authors have contributed equally to this work Correspondence to: Wei-Chien Huang, e-mail: whuang@mail.cmu.edu.tw Keywords: lapatinib, IL-6, migration, microRNA, Raf-1 Received: April 23, 2015 Accepted: October 02, 2015 Published: October 12, 2015 ABSTRACT Lapatinib, a dual epidermal growth factor receptor (EGFR) and HER2 tyrosine kinase inhibitor (TKI), has been approved for HER2-positive breast cancer patients. Nevertheless, its inhibitory effect on EGFR did not deliver clinical benefits for triple-negative breast cancer (TNBC) patients even EGFR overexpression was frequently found in this disease. Moreover, lapatinib was unexpectedly found to enhance metastasis of TNBC cells, but the underlying mechanisms are not fully understood. In this study, we explored that the level of interleukin-6 (IL-6) was elevated in lapatinib-treated TNBC cells. Treatment with IL-6 antibody abolished the lapatinib-induced migration. Mechanistically, the signaling axis of Raf-1/mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinases (JNKs), p38 MAPK, and activator protein 1 (AP-1) was activated in response to lapatinib treatment to induce IL-6 expression. Furthermore, our data showed that microRNA-7 directly binds and inhibits Raf-1 3′UTR activity, and that down-regulation of miR-7 by lapatinib contributes to the activation of Raf-1 signaling pathway and the induction of IL-6 expression. Our results not only revealed IL-6 as a key regulator of lapatinib-induced metastasis, but also explored the requirement of miR7/Raf-1/MAPK/AP-1 axis in lapatinib-induced IL-6 expression.

Although radiation therapy was known to be effective to cervical cancer, loco-regional recurrences are frequently found in patients. We aimed to identify a molecular marker predicting the response of cervical cancer to radiotherapy. We included the patients (n = 149) with cervical cancer who had undergone radiotherapy from 2004 to 2006. Tumor samples were collected to examine the association between the expression of S-phase kinase-associated protein 2 (SKP2) and prognosis in cervical cancer. We found higher expression of SKP2 associated with recurrence (HRs: 2.52, p0.001), death (HRs: 2.01, p0.001) and higher locoregional recurrence rate (HRs: 3.76, p0.001). Cervical cancer cell lines with higher expression of SKP2 showed higher colony formation, cell survival rate and fewer DNA damages after irradiation. SKP2-C25, an inhibitor for SKP2 activity, dose-dependently decreased cell viability after irradiation and knockdown of SKP2 impaired DNA-damage response and sensitized the cervical cancer cells to irradiation. Our data showed the SKP2 represents a promising tool to identify patients with cervical cancer who have a higher risk of locoregional recurrence after radiotherapy. Targeting SKP2 may serve as a potential radiosensitizer for developing effective therapeutic strategies against cervical cancer.