Oncology Research 20(5-6) Abstracts

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Oncology Research, Vol. 20, pp. 187–195, 2013
0965-0407/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504013X13589503482699
E-ISSN 1555-3906
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Simvastatin Downregulates HER2 via Upregulation of PEA3 to Induce Cell Death in HER2-Positive Breast Cancer Cells

Zhen Zhao, Xiangming Cao, Yukai Pan, Sha Sha, Tao Zhao, and Tingrong Zhang

Department of Oncology, the Affiliated Jiangyin Hospital of Southeast University Medical College, Wuxi, Jiangsu, P.R. China

Simvastatin is a widely used cholesterol-adjusting drug that selectively inhibits the 3-hyrdoxy-3-methylglutaryl-coenzyme A reductase, leading to decreased cholesterol biosynthesis. Notably, through this activity, simvastatin exerts antiproliferative and proapoptotic effects on various cancer cells, including non-small cell lung and breast cancer. Although statin-induced breast cancer cell death is nitric oxide inducible and arginase dependent, we report alternative mechanisms relative to the antitumor function of simvastatin in breast cancer cells. Simvastatin induced cell death in MDA-MB-361, SK-Ov3, and SKBR3, HER2-overexpressing cell lines, in both time- and dose-dependent manners, but did not exert cytotoxicity in MCF10A and MDAMB-231, HER2 low/negative cell lines. The protein expression of HER2 decreased after the cells were treated with simvastatin; however, HER2 protein and mRNA stabilities were not changed. Furthermore, simvastatin inhibited the activity of the HER2 promoter. Simvastatin-induced cytotoxicity and promoter activity repression were reversed by mevalonate and GGPP, the immediate metabolic products of the acetyl CoA/3-hyrdoxy-3-methylglutaryl CoA reductase reaction and the isoprenoid of the mevalonate cascade, respectively. In addition, simvastatin treatment induced the expression of PEA3, which is a HER2 promoter inhibitor. The use of siRNA to downregulate expression of PEA3 inhibited the simvastin-induced HER2 repression and cell death. These findings provide alternative mechanisms for the antitumor effects of simvastatin, suggesting that simvastatin could also be used as a combination therapy with other chemotherapy agents in HER2-positive patients.

Key words: Simvastatin; HER2; PEA3; Cell death; Breast cancer cells

Address correspondence to Zhen Zhao, M.D., Department of Oncology, the Affiliated Jiangyin Hospital of Southeast University Medical College, 163 Shoushan Road, Wuxi, Jiangsu 214400, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 197–203, 2013
0965-0407/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504013X13589503482734
E-ISSN 1555-3906
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

MicroRNA-375 Is Downregulated in Pancreatic Cancer and Inhibits Cell Proliferation In Vitro

Jian Zhou,*1 Shiduo Song,*1 Jiannong Cen,† Dongming Zhu,* Dechun Li,* and Zixiang Zhang*

*The Department of General Surgery, the First Affiliated Hospital of Soochow University, Suzhou, P.R. China
†Jiangsu Institute of Hematology, Suzhou, P.R. China

MicroRNAs (miRNAs) have emerged as important regulators in the development of pancreatic cancer and may be a valuable therapeutic application. Aberrant expression of microRNA-375 (miR-375) has been reported to be involved in development and progression in various types of cancers, but few studies have been conducted to determine its relationship with pancreatic cancer. Quantitative RT-PCR was used to detect the levels of miR-375 expression in pancreatic cancer tissue samples and cells. The cell growth rate of pancreatic cancer cells transfected with pre-miR-375 was examined by CCK8 assay. The effects of miR-375 on cell cycle and apoptosis were assessed by flow cytometry analyses. In this study, we found that the expression levels of miR-375 was significantly lower in pancreatic cancer tissues compared with nontumorous tissues. We found that miR-375 level in pancreatic cancer was associated with lymph nodes metastasis and clinical stage, and did not correlated with any other factors such as sex, age, position, tumor size, or histological grading. The CCK8 assay showed that that cells transfected with pre-miR-375 inhibited cell proliferation in Panc-1 and SW1990 cells. Flow cytometry analysis indicated that upregulation of miR-375 led to an increase in the percentage of cells in G0/G1 phase in the cell cycle distribution and induced cell apoptosis. Our research suggested that miR-375 has potential as a novel suppressor gene in pancreatic cancer and its downregulation may promote the progression of pancreatic cancer. Overexpression of miR-375 impacts cell proliferation, cell cycle distribution, and apoptosis of pancreatic cancer cells. miR-375 may play an important role in the novel therapeutic strategy for pancreatic cancer.

Key words: Pancreatic cancer; MicroRNA-375; Clinicopathological features; Apoptosis

1These authors provided equal contribution to this work and should be considered co-first authors.
Address correspondence to Zixiang Zhang, M.D., Department of General Surgery, the First Affiliated Hospital of Soochow University, Suzhou 215006, P.R. China. Tel: +86-512-67780107; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 205–211, 2013
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DOI: http://dx.doi.org/10.3727/096504013X13589503482770
E-ISSN 1555-3906
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

LRIG1 Enhances Cisplatin Sensitivity of Glioma Cell Lines

Xiongwei Wang,*†1 Qungen Xiao,‡1 Xihong Xing,*† Chunlei Tian,*† Huaqiu Zhang,‡ Fei Ye,‡ Feng Wan,‡ Baofeng Wang,‡ Dongsheng Guo,‡ and Ting Lei‡

*Institute of Neurology, The First College of Clinical Medical Science, China Three Gorges University, Yichang, China
†Department of Neurosurgery, Yichang Center People’s Hospital, Yichang, China
‡Department of Neurosurgery and Sino-German Neuro-Oncology Molecular Laboratory, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

LRIG family shares similar structures that include a signal peptide, an extracellular region consisting of a leucine-rich repeat domain and three immunoglobulin-like domains, a transmembrane domain, and a cytoplasmic tail. After activation of EGFR, the extracellular LRR domain and immunoglobulin-like domains of LRIG1 can bind to the extracellular parts of EGFR, resulting in recruitment of c-Cbl to the cytoplasmic domains, and induction of EGFR degradation. This study investigated the effects of overexpression of leucine-rich repeats and LRIG1 on cisplatin (CDDP) sensitivity in the glioma cell line U251 and explored the possible mechanisms mediating this effect. We found that CDDP could inhibit the growth of U251 cell line and induced activation of the EGFR. Overexpression of LRIG1 increased the inhibitory effect of CDDP on the U251 cell line via the inhibition of proliferation and induction of apoptosis. The mechanisms underlying the effect of the combined treatment of LRIG1 and CDDP could be that LRIG1 blocked CDDP-induced EGFR activation and regulated the apoptosis proteins. These findings suggest that upregulation of LRIG1expression enhances the CDDP sensitivity in the glioma cell line U251.

Key words: LRIG1; EGFR; Glioma; Cisplatin

1These authors provided equal contribution to this work.
Address correspondence to Dongsheng Guo, M.D., Ph.D., Department of Neurosurgery and Sino-German Neuro-Oncology Molecular Laboratory, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 213–220, 2013
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DOI: http://dx.doi.org/10.3727/096504013X13589503482815
E-ISSN 1555-3906
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Hypoxia-Inducible Factor-1α Suppressed Hepatocellular Carcinoma Cell Apoptosis Through Influencing on Omi/HtrA2 Expression and Its Releasing From the Mitochondrion

Zongquan Xu,* Xiaoping Chen,† Cheng Peng,* Enyu Liu,* Yunguang Li,* Changhai Li,† and Jun Niu*

*Hepatobiliary Surgery Qilu Hospital, ShanDong University, Jinan, China
†Hepatic Surgery Center Affiliated Tongji Hospital, Tongji Medical College of Hua Zhong University of Science and Technology, Wuhan, China

Hypoxia-inducible factor-1α (HIF-1α) plays an important role in regulating hepatoma cell apoptosis. However, conclusions of different studies about the effects of HIF-1α expression on hepatoma cell apoptosis remain controversial. Omi/HtrA2 promotes cell apoptosis in some human cancer cells. Our previous experiments have demonstrated that primary hepatocellular carcinoma may need Omi/HtrA2 expression for cell apoptosis. Thus, we investigated the effect of HIF-1α on hepatocellular carcinoma cell apoptosis and Omi/HtrA2 expression. In our study we found that HIF-1α gene could suppress hepatoma cell apoptosis, and Omi/HtrA2 mRNA and protein expression decreased with HIF-1α expression increase while Bcl-2 mRNA and protein expression increased with HIF-1α expression increase in HepG2 cells under normoxia condition. Meanwhile, Omi/HtrA2 protein expression increased with HIF-1α expression decrease in HepG2 cells under hypoxia culture. Taken together, these results demonstrated that HIF-1α suppressed hepatocellular carcinoma cell apoptosis through inhibiting Omi/HtrA2 expression and upregulating Bcl-2 expression to impede Omi/HtrA2 releasing from the mitochondrion. The present finding further enriched and supported the role of HIF-1α expression on cell apoptosis of hepatoma cells.

Key words: Hypoxia-inducible factor-1α (HIF-1α); Omi/HtrA2; HepG2 cell apoptosis

Address correspondence to Jun Niu, Hepatobiliary Surgery Qilu Hospital, ShanDong University, Jinan 250012, China. Tel: +86 531 82169203; Fax: +86 531 82169243; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 221–229, 2013
0965-0407/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504013X13589503482897
E-ISSN 1555-3906
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

The Relationship Between EGFR Gene Mutation Status and ERCC1 in Lung Adenocarcinoma of Chinese Patients Receiving Platinum-Based Neoadjuvant Chemotherapy

Hong-Gang Ke,*† Xiao-Yu Zhou,‡ Yi Shen,§ Qing-Sheng You,† Yu Yan,† and Zhen-Ya Shen*

*Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Soochow University, SuZhou, JiangSu Province, China
†Department of Thoracic Surgery, The Affiliated Hospital of NanTong University, NanTong, JiangSu Province, China
‡Department of Respiratory Medicine, The Affiliated Hospital of NanTong University, NanTong, JiangSu Province, China
§Department of Statistical Research, NanTong University, NanTong, JiangSu Province, China

The specific aim of this study was to assess the relationship between the mutation status of the epidermal growth factor receptor (EGFR) gene and excision repair cross-complementation group 1 (ERCC1) in lung adenocarcinoma of patients that received platinum-based neoadjuvant chemotherapy. One hundred and seven primary lung adenocarcinoma patients with 22 stage IIa, 61 stage IIb, and 24 stage IIIa (TNM staging 2009) were included in this study. EGFR genetic mutations including exon 19 and 21 were detected by direct polymerase chain reaction (PCR) sequencing and compared with various clinical/pathologic features. Immunohistochemistry was performed to detect the expression of ERCC1 compared to EGFR mutation status in tumors. The frequency of EGFR mutations before and after chemotherapy was 64.3% (61/107) and 73.2% (70/107), respectively. The mutation frequency of exon 19 and 21 were 60.7% (37/61) and 39.3% (24/61) prior to chemotherapy, compared to 58.6% (41/70) and 41.4% (29/70) after chemotherapy. Mutations in EGFR were significantly different in females (prechemo: p = 0.003 vs. postchemo: p = 0.012) and nonsmokers (prechemo: p = 0.007 vs. postchemo: p = 0.000). Positive expression of ERCC1 was higher in patients with unchanged EGFR mutation status (28.4%, 25/88) than that in patients with altered mutation status (26.3%, 5/19) (p = 0.021). Log rank analysis indicated that disease-free survival was influenced by EGFR mutation status. Patients with an unchanged EGFR mutational status after chemotherapy were more likely to express ERCC1, and this change may serve as a clinical indicator of therapy response.

Key words: EGFR; ERCC1; Mutation; Lung adenocarcinoma; Chemotherapy

Address correspondence to Zhen-Ya Shen, Ph.D., Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Soochow University, SuZhou 100015, JiangSu Province, China. Tel: 86-0512-67780100; Fax: 86-0512-67780100; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 231–240, 2013
0965-0407/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504013X13589503482932
E-ISSN 1555-3906
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Inhibition of Cellular Growth and Migration by Suppression of Endothelial Protein C Receptor (EPCR) in Lung Carcinoma Cells

Wei Heng,* Jian-An Huang,* and Zhao-Yue Wang†

*Respiratory Department, the First Affiliated Hospital of Soochow University, Suzhou, China
†Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, China

Increasing evidence shows that beyond its role in coagulation, thrombosis interferes with carcinogenesis. Endothelial cell protein C receptor (EPCR) is a cellular receptor for protein C and activated protein C (APC). Such EPCR-induced signal transduction promotes cancer cell migration, invasion, and angiogenesis and inhibits cancer cell apoptosis. However, its role in lung carcinoma biology is yet to be demonstrated. Here, the recombinant EPCR siRNA plasmids were constructed to investigate the effects of inhibition of EPCR on human lung cancer H1299. EPCR siRNA led to inhibition of endogenous EPCR mRNA and protein expression as determined by RT-PCR and Western blotting analysis. EPCR siRNA significantly inhibited cell growth, blocked entry into the S phase of the cell cycle, and reduced the migration of H1299 cells. EPCR siRNA also decreases MMP-2 and cyclin E expression in H1299 cells. In addition, siRNA targeting of EPCR inhibited the growth of H1299 cells and decreased MVD in SCID mice tumor models. Taken together, EPCR was involved in regulating progression of human lung cancer cells. Manipulation of EPCR expression may be a potential therapeutic strategy for lung cancer.

Key words: EPCR; Lung cancer; Growth; Small interference RNA

Address correspondence to Dr. Wei Heng, Respiratory Department, the First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 241–250, 2013
0965-0407/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504013X13589503482978
E-ISSN 1555-3906
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Gene Amplification and Overexpression of Aurora-C in Breast and Prostate Cancer Cell Lines

Ali Zekri,* Vahid Lesan,† Seyed H. Ghaffari,‡ Mina Hajifaraj Tabrizi,* and Mohammad Hussein Modarressi*

*Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran
†Departmant of Toxicology, Faculty of Veterinary Medicine, Tehran University, Tehran, Iran
‡Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran

Human aurora kinases are three highly conserved serine/threonine kinases with regulatory function in chromosome alignment, chromosome segregation, and cytokinesis during cell cycle progression and their overexpression associates with malignant transformation and proliferation of cancer cells. Aurora genes are located at loci that are commonly altered in cancers. Aurora-A has oncogenic activity while Aurora-B does not. Aurora-C is only detected in mammals with involvement in meiosis. Oncogenic activity of Aurora-C is still in dispute. We evaluated the expression of three Aurora kinases by real-time RT-PCR in well-known breast and prostate cancer cell lines. Cell cycle was studied with flow cytometry. In both more invasive cell lines’ p53-null cells, PC-3 and MDA-MB-231, an increase in mRNA expression of three Aurora kinases, especially Aurora-C, was observed. Genomic DNA was examined for gene amplification and aneuploidy as a mechanism of overexpression. At DNA level, only Aurora-C showed gene amplification in breast cancer cell lines (p < 0.005). Here we provide evidence for the first time of Aurora-C overexpression and gene amplification.

Key words: Aurora-C kinase; Gene amplification; mRNA overexpression; Cancer

Address correspondence to Mohammad H. Modarressi, M.D., Ph.D., Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 251–258, 2013
0965-0407/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504013X13589503483012
E-ISSN 1555-3906
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Hypoxia-Induced Autophagy Confers Resistance of Breast Cancer Cells to Ionizing Radiation

Wen-Shan He,* Xiao-Fang Dai,† Min Jin,† Cui-Wei Liu,† and Jing-Hua Ren†

*Department of General Surgery, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
†Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China

Hypoxia is a hallmark of solid tumors, which presents a major obstacle to the effectiveness of radiation therapy. However, the function and the importance of molecular response have not been well defined. In the present study, hypoxia-induced autophagy and its effect on the response of breast cancer cells to ionizing radiation were examined. Results showed that hypoxic exposure induced a marked accumulation of autophagosomes accompanied by mRNA induction of the autophagy-related genes Beclin-1, Atg5, Atg7, and Atg12. The elevated autophagic activity was associated with increased radioresistance of tumor cells. Accordingly, blockade of autophagy by pharmacological inhibition or Beclin-1 small interfering RNA (siRNA) contributed to retardation of DNA double-strand breaks (DSB) repair and significant radiosensitization. Our data indicate that strategies designed to suppress autophagic activity may represent promising new therapies for sensitizing hypoxic breast cancer cells to ionizing radiation (IR).

Key words: Autophagy; Breast cancer; Radioresistance; RNA interference

Address correspondence to Jing-Hua Ren, Ph.D., Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, P.R. China. Tel: +86-27-85873100; Fax: +86-27-65650733; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 259–264, 2013
0965-0407/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504013X13589503482851
E-ISSN 1555-3906
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Case Report

The Efficacy and Tolerability of a Sunitinib 3-Week Administration Schedule in Metastatic Renal Cell Carcinoma Patients: Report of Three Cases

B. Neri, A. Vannini, R. Tassi, M. Brugia, S. Rangan, M. Rediti, and C. Cerullo

Department of Oncology, Centre of Experimental and Clinical Oncology, AOU-Careggi, Florence University, Florence, Italy

Sunitinib, an orally multitargeted tyrosine kinase inhibitor and standard first-line treatment for metastatic renal cell carcinoma, is usually administered on a 6-week schedule. Toxicities reported with this drug are usually of moderate grade, which results in good treatment tolerability and patients’ compliance. However, in some cases high-grade or prolonged toxicities require temporary treatment interruption or dose adjustment, possibly resulting in reduced treatment efficacy. We describe three cases of metastatic renal cell carcinoma patients (a 53-year-old male, a 70-year-old woman, and a 65-year-old woman) who received a shortened 3-week sunitinib administration schedule, 2 weeks daily administration followed by 1 week of rest (2/1) due to toxicities developed on the classic 6-week schedule, which would have required a temporary treatment interruption or a dose reduction. Treatment was generally well tolerated with manageable toxicities. A 3-week administration schedule of sunitinib may represent a valid alternative for managing toxicity while maintaining the planned dose intensity over a 6-weeks period of time. Sunitinib may thus be administered using a flexible dosing schedule to meet individual patient needs, achieving better tolerability and maintaining significant response to treatment.

Key words: Sunitinib; Metastatic renal cell carcinoma; 3-Week schedule

Address correspondence to Prof. Bruno Neri, M.D., Associate of Medical Oncology, Department of Oncology, Centre of Experimental and Clinical Oncology, Azienda Ospedaliero Universitaria Careggi, L.go G. Brambilla 3, 50134, Florence, Italy. Tel/fax: +390557949748; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it