Oncology Research 22(1) Abstracts

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Oncology Research, Vol. 22, pp. 1–12, 2014
0965-0407/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504014X14077751730270
E-ISSN 1555-3906
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

ENOX2 Target for the Anticancer Isoflavone ME-143

D. James Morré, Theodore Korty, Christiaan Meadows, Laura M. C. Ades, and Dorothy M. Morré

Mor-NuCo, Inc., West Lafayette, IN, USA

ME-143 (NV-143), a synthetic isoflavone under clinical evaluation for efficacy in the management of ovarian and other forms of human cancer, blocked the activity of a cancer-specific and growth-related cell surface ECTO-NOX protein with both oxidative (hydroquinone) and protein disulfide-thiol interchange activity designated ENOX2 (tNOX) and inhibited the growth of cultured cancer cells with EC50s in the range of 20–50 nM. Purified recombinant ENOX2 also bound ME-143 with a Kd of 43 (40–50) nM. Both the oxidative and protein disulfide-thiol interchange activities of ENOX proteins that alternate to generate a complex set of oscillations with a period length of 22 min compared to 24 min for the constitutive counterpart ENOX1 (CNOX) that characterizes ENOX proteins responded to ME-143. Oxidation of NADH or reduced coenzyme Q10 was rapidly blocked. In contrast, the protein disulfide-thiol interchange activity measured from the cleavage of dithiodipyridine (EC50 of ca. 50 nM) was inhibited progressively over an interval of 60 min that spanned three cycles of activity. Inhibition of the latter paralleled the inhibition of cell enlargement and the consequent inability of inhibited cells to initiate traverse of the cell cycle. Activities of constitutive ENOX1 (CNOX) forms of either cancer or noncancer cells were unaffected by ME-143 over the range of concentrations inhibiting ENOX2. Taken together, the findings show that ME-143 binds to ENOX2 with an affinity 4 to 10 times greater than that reported previously for the related anticancer isoflavone, phenoxodiol.

Key words: ENOX; NADH oxidase; ENOX2; Cancer; ME-143; NV-143; Phenoxodiol; Isoflavone; tNOX

Address correspondence to D. James Morré, Mor-NuCo, Inc., 1201 Cumberland Avenue, Suite B, Purdue Research Park, West Lafayette, IN 47906, USA. Tel: +1-765-491-4876; Fax: +1-765-464-8769; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 22, pp. 13–20, 2014
0965-0407/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504014X14077751730315
E-ISSN 1555-3906
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Fulvestrant-Mediated Inhibition of Estrogen Receptor Signaling Slows Lung Cancer Progression

Hexiao Tang,*† Yongde Liao,* Chao Zhang,*‡ Guang Chen,*§ Liqiang Xu,*¶ Zhaoguo Liu,† Shengling Fu,* Li Yu,† and Sheng Zhou#

*Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
†Department of Intensive Care Unit, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
‡Department of Respiratory Medicine, The Central Hospital of Yichang, Yichang, China
§Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
¶Department of Thoracic Surgery, Taihe Hospital, Hubei University of Medicine, Shiyan, China
#Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

Estrogens are key signaling molecules that regulate various physiological processes such as cell growth, development, and differentiation. They also play a major role in many pathological conditions, such as hormone-dependent cancer. The importance of inhibiting estrogen receptor signaling in diseases of estrogen target tissues, such as breast cancer, is well documented. However, the role of estrogen signaling in diseases of nontarget tissues, such as lung cancer, is not well characterized. The aim of the current study is to examine the expression of estrogen receptor β (ERβ) and the roles of estradiol (E2) and fulvestrant on the progression of lung cancer. Tissue microarray (TMA) and immunohistochemistry (IHC) analyses were used to detect the expression of aromatase, ERα, and ERβ in 198 patients. We performed analyses to determine if there was any correlation among these three proteins. A mouse model of urethane-induced lung adenocarcinoma was used in the study. Mice were divided into three treatment groups: blank control, E2 alone, and E2 + fulvestrant (ERβ antagonist). Western blot analysis and fluorescence quantitative PCR (FQ-PCR) were used to measure expression of ERβ protein and mRNA levels, respectively. ERβ, but not ERα, was overexpressed in NSCLC samples. Lung cancer progression in mice treated with E2 was significantly increased compared to either the control group or the E2 + fulvestrant group. Mice in the E2 treatment group had significantly increased expression of ERβ at both the mRNA and protein levels compared to mice treated with E2 + fulvestrant or control. Our data suggest that ERβ promotes lung cancer progression in mice and that this progression can be inhibited with fulvestrant. These findings may help elucidate the role of ERβ in lung cancer and suggest that estrogen receptor antagonists, such as fulvestrant, may be therapeutically beneficial for the treatment of the disease.

Key words: Lung cancer; Mouse model; Estrogen receptor β (ERβ); Fulvestrant; Tissue microarray; Immunohistochemistry

Address correspondence to Yongde Liao, Department of Thoracic Surgery, Tongji Hospital, Jiefang Dadao Street 1095, Wuhan, Hubei Province, China 430030. Tel: +086 15972212919; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 22, pp. 21–28, 2014
0965-0407/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504014X14077751730351
E-ISSN 1555-3906
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

TRAF4 Enhances Osteosarcoma Cell Proliferation and Invasion by Akt Signaling Pathway

Weitao Yao, Xin Wang, Qiqing Cai, Songtao Gao, Jiaqiang Wang, and Peng Zhang

Department of Bone and Soft Tumor, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China

TRAF4, or tumor necrosis factor receptor-associated factor 4, is overexpressed in several cancers, suggesting a specific role in cancer progression. However, its functions in osteosarcoma are unclear. This study aimed to explore the expression of TRAF4 in osteosarcoma tissues and cells, the correlation of TRAF4 to clinical pathology of osteosarcoma, as well as the role and mechanism of TRAF4 in osteosarcoma metastasis. The protein expression levels of TRAF4 in osteosarcoma tissues and three osteosarcoma cell lines, MG-63, HOS, and U2OS, were assessed. Constructed TRAF4 overexpression vectors and established TRAF4 overexpression of the U2OS cell line. Cell proliferation, cell invasion, protein levels, and TRAF4 phosphorylations were assessed following TRAF4 transfection, as well as the effects of TRAF4 siRNA on cell proliferation and invasion. The results show that TRAF4 protein levels in osteosarcoma tissues were significantly higher than that in normal bone tissues. Importantly, an obvious upregulation of TRAF4 was found in carcinoma tissues from patients with lung metastasis compared with patients without lung metastasis. Consistently, a similar increase in TRAF4 mRNA and protein was also demonstrated in the osteosarcoma cell lines MG-63, HOS, and U2OS compared to normal bone cells, hFOB1.19. When TRAF4 was overexpressed in U2OS cells, cell proliferation was significantly enhanced, accompanied by an increase in Ki67 expression and colony formation. Compared with the control and vector-treated groups, TRAF4 transfection increased the invasion potential of U2OS cells (p < 0.05). Interestingly, TRAF4 transfection significantly enhanced the phosphorylation of Akt. After blocking Akt with its specific siRNA, TRAF4-induced cell proliferation and invasion were dramatically attenuated. In summary, our findings demonstrated that TRAF4 enhances osteosarcoma cell proliferation and invasion partially by the Akt pathway. This work suggests that TRAF4 might be an important target in osteosarcoma.

Key words: Osteosarcoma; TRAF4; Cell proliferation; Cell invasion; Akt signaling pathway

Address correspondence to Weitao Yao, Department of Bone and Soft Tumor, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 45000, China. Tel/Fax: +86- 037165587728; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 22, pp. 29–37, 2014
0965-0407/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504014X14078436004987
E-ISSN 1555-3906
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

FOXM1 Regulated by ERK Pathway Mediates TGF-β1-Induced EMT in NSCLC

Fei-Fei Kong,*1 You-Long Zhu,†1 Hai-Hua Yuan,* Jiong-Yi Wang,* Mei Zhao,* Xiao-Di Gong,* Feng Liu,* Wen-Ying Zhang,* Cong-Rong Wang,‡ and Bin Jiang*

*Department of Oncology, Shanghai 3rd People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
†Department of General Surgery, Shanghai 3rd People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
‡Metabolic Disease Bio-Bank, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China

FOXM1, a member of the Forkhead transcriptional family, plays an important role in the EMT process, and transforming growth factor-β1 (TGF-β1) has been identified as the most potent factor that can independently induce EMT in various types of cancer cells. Here we examine the important role of FOXM1 in TGF-β1-induced EMT and investigate the mechanism underlying the relationship between TGF-β1 and FOXM1. Lentivirus-mediated transfection was used to stably upregulate the expression of FOXM1, and a small interfering RNA (siRNA) was introduced to silence the expression of FOXM1. Transwell and wound-healing assays were then performed to assess the invasion and motility potential of non-small cell lung cancer (NSCLC) cells. The NSCLC cell lines exhibited EMT characteristics, including an elongated fibroblastoid shape, induced expression of EMT marker proteins, and increased migratory and invasive potential after induction with TGF-β1. The overexpression of FOXM1 enhanced TGF-β1-induced EMT in NSCLC cells. Knockdown of FOXM1 reversed TGF-β1-induced EMT in NSCLC cell lines but had no effect on the phosphorylation level of ERK. Additionally, U0126, an ERK signaling inhibitor, exerted a reversible effect on TGF-β1-induced EMT and inhibited FOXM1 expression. FOXM1 regulated by the ERK pathway can mediate TGF-β1-induced EMT in NSCLC and is a potential target for the treatment of NSCLC.

Key words: FOXM1; Epithelial–mesenchymal transition (EMT); TGF-β1; ERK; Non-small cell lung cancer

1These authors provided equal contribution to this work.
Address correspondence to Professor Bin Jiang, Department of Oncology, Shanghai 3rd People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 201900, China. Tel: +86-21-56691101-6944; Fax: +86-21-56693614; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Professor Cong-Rong Wang, Metabolic Disease Bio-Bank, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai 200233, China. Tel: +86-21-24058254; Fax: +86-21-24058254; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 22, pp. 39–45, 2014
0965-0407/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504014X14078436005012
E-ISSN 1555-3906
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Knockdown of Tripartite Motif Containing 24 by Lentivirus Suppresses Cell Growth and Induces Apoptosis in Human Colorectal Cancer Cells

Jianwei Wang,* Jinhui Zhu,* Mingjun Dong,† Hua Yu,† Xiaoyu Dai,† and Keqiang Li‡

*Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
†Department of Anorectal Surgery, Ningbo Second Hospital, Ningbo, China
‡Clinical Research Center, Ningbo Second Hospital, Key Laboratory of Molecular Biology of Cancer, Ningbo, China

Colorectal cancer remains one of the most common cancers in men and women, and it accounts for a large proportion of cancer-related deaths worldwide. Tripartite motif (TRIM) proteins are a novel class of “single protein RING finger” E3 ubiquitin ligases, which have been shown to be involved in many cancers. The aim of this study was to investigate the potential role of TRIM24 in human colorectal cancer. By using a lentivirus-mediated RNA interference system, we first explored the effect of TRIM24 knockdown on HCT116 cell proliferation and colony formation. Moreover, flow cytometry analysis was used to examine its effects on cell cycle distribution and apoptosis. Our data showed that knockdown of TRIM24 expression in HCT116 cells significantly decreased cell growth due to the induction of apoptosis. Hence, the present study provides evidence that TRIM24 functions as an oncogene in colorectal carcinogenesis.

Key words: TRIM24; Proliferation; Apoptosis; Colorectal cancer; Lentivirus

Address correspondence to Xiaoyu Dai, Department of Anorectal Surgery, Ningbo Second Hospital, 41 Northwest Street, Ningbo 315010, China. Tel/Fax: +86-0574-83870317; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Keqiang Li, Clinical Research Center, Ningbo Second Hospital, Key Laboratory of Molecular Biology of Cancer, 41 Northwest Street, Ningbo 315010, China. Tel/Fax: +86-0574-83870439; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 22, pp. 47–55, 2014
0965-0407/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504014X14098532393473
E-ISSN 1555-3906
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Epithelial–Mesenchymal Transition Contributes to Docetaxel Resistance in Human Non-Small Cell Lung Cancer

Weiwei Shen,1 Hailin Pang,1 Jiayu Liu, Jing Zhou, Feng Zhang, Lele Liu, Ningqiang Ma, Ning Zhang, Helong Zhang, and Lili Liu

Department of Oncology, Tangdu Hospital, the Fourth Military Medical University, Xi’an, Shaanxi, China

Lung cancer is an aggressive malignancy with high morbidity and mortality. Chemotherapy has always been the principal treatment measure, but its acquired resistance becomes a critical problem. In the current study, we established a new docetaxel-resistant human non-small lung cancer (NSCLC) cell line A549/Docetaxel. The resistance index (RI) of A549/Docetaxel cells and A549 induced by TGF-β to docetaxel were 8.91 and 11.5, respectively. Compared to the parental A549 cells, the multiplication time of A549/Docetaxel was prolonged, the proportion of the cell cycle in the S phase decreased while that in the G1 phase increased, and apoptotic rate was much lower. The morphology of the resistant cells eventuated epithelial–mesenchymal transition (EMT), which was confirmed by the higher expression of fibronectin, vimentin (mesenchymal markers), and lower expression of E-cadherin (epithelial marker) at mRNA and proteins levels. Furthermore, the representative markers for docetaxel resistance were examined, including ABCB1 (MDR1), Bcl-2, Bax, and tubulin, to figure out the mechanisms of the resistance of A549/Docetaxel. In summary, we have established a typical docetaxel-resistant human NSCLC cell line A549/Docetaxel, and it was suggested that the multidrug resistance of A549/Docetaxel was related to EMT.

Key words: Epithelial–mesenchymal transition (EMT); Human non-small cell lung cancer; Docetaxel; Drug resistance

1These authors provided equal contribution to this work.
Address correspondence to Helong Zhang, Professor, Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710038, China. Tel: +13519128910; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Lili Liu, Professor, Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710038, China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 22, pp. 57–65, 2014
0965-0407/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504014X14098532393518
E-ISSN 1555-3906
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Blockage of Potassium Channel Inhibits Proliferation of Glioma Cells Via Increasing Reactive Oxygen Species

Li Hu, Li-Li Li, Zhi-Guo Lin, Zhi-Chao Jiang, Hong-Xing Li, Shi-Guang Zhao, and Kong-Bin Yang

Department of Neurosurgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China

The potassium (K+) channel plays an important role in the cell cycle and proliferation of tumor cells, while its role in brain glioma cells and the signaling pathways remains unclear. We used tetraethylammonium (TEA), a nonselective antagonist of big conductance K+ channels, to block K+ channels in glioma cells, and antioxidant N-acetyl-L-cysteine (NAC) to inhibit production of intracellular reactive oxygen species (ROS). TEA showed an antiproliferation effect on C6 and U87 glioma cells in a time-dependent manner, which was accompanied by an increased intracellular ROS level. Antioxidant NAC pretreatment reversed TEA-mediated antiproliferation and restored ROS level. TEA treatment also caused significant increases in mRNA and protein levels of tumorsuppressor proteins p53 and p21, and the upregulation was attenuated by pretreatment of NAC. Our results suggest that K+ channel activity significantly contributes to brain glioma cell proliferation via increasing ROS, and it might be an upstream factor triggering the activation of the p53/p21Cip1-dependent signaling pathway, consequently leading to glioma cell cycle arrest.

Key words: Glioma; Potassium channel blocker; Cell proliferation; Reactive oxygen species (ROS)

Address correspondence to Kongbin Yang, M.D., Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150001, P.R. China. Tel: +86-451-85555880; +86-18045100688; Fax: +86-451-53670428; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it