Oncology Research 24(1) Abstracts

Return to Oncology Research>

Oncology Research, Vol. 24, pp. 1-7, 2016
0965-0407/16 $90.00
+ .00
DOI: http://dx.doi.org/10.3727/096504016X14570992647087
E-ISSN 1555-3906
Copyright
© 2016 Cognizant, LLC. 
Printed in the USA. All rights reserved

Radiosensitization of Non-Small Cell Lung Cancer Cells by Inhibition of TGF-β1 Signaling With SB431542 Is Dependent on p53 Status

Yifan Zhao,*†1 Longxiao Wang,*1 Qianyi Huang,*‡ Youqin Jiang,* Jingdong Wang,* Liyuan Zhang,‡§ Ye Tian,‡§ and Hongying Yang*§

*School of Radiation Medicine and Protection, Medical College of Soochow University/Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, Jiangsu, China
†College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
‡Department of Radiotherapy and Oncology, Second Affiliated Hospital, Soochow University, Suzhou, Jiangsu, China
§Institute of Radiotherapy and Oncology, Soochow University, Suzhou, Jiangsu, China

Although medically inoperable patients with stage I non-small cell lung cancer cells (NSCLC) are often treated with stereotactic body radiation therapy, its efficacy can be compromised due to poor radiosensitivity of cancer cells. Inhibition of transforming growth factor-
β1 (TGF-β1) using LY364947 and LY2109761 has been demonstrated to radiosensitize cancer cells such as breast cancer, glioblastoma, and lung cancer. Our previous results have demonstrated that another potent and selective inhibitor of TGF-β1 receptor kinases, SB431542, could radiosensitize H460 cells both in vitro and in vivo. In the present study, we investigated whether SB431542 could radiosensitize other NSCLC cell lines, trying to explore the potential implication of this TGF-β1 inhibitor in radiotherapy for NSCLC patients. The results showed that A549 cells were significantly radiosensitized by SB431542, whereas no radiosensitizing effect was observed in H1299 cells. Interestingly, both H460 and A549 cells have wild-type p53, while H1299 cells have deficient p53. To study whether the radiosensitizing effect of SB431542 was associated with p53 status of cancer cells, the p53 of H460 cells was silenced using shRNA transfection. Then it was found that the radiosensitizing effect of SB431542 on H460 cells was not observed in H460 cells with silenced p53. Moreover, X-irradiation caused rapid Smad2 activation in H460 and A549 cells but not in H1299 and H460 cells with silenced p53. The Smad2 activation postirradiation could be abolished by SB431542. This may explain the lack of radiosensitizing effect of SB431542 in H1299 and H460 cells with silenced p53. Thus, we concluded that the radiosensitizing effect of inhibition of TGF-β1 signaling in NSCLC cells by SB431542 was p53 dependent, suggesting that using TGF-b1 inhibitor in radiotherapy may be more complicated than previously thought and may need further investigation.

Key words: Radiosensitization; Non-small cell lung cancer cells (NSCLC); Transforming growth factor-β1 (TGF-β1); SB431542; p53 status

1These authors provided equal contribution to this work.
Address correspondence to Hongying Yang, School of Radiation Medicine and Protection, Medical College of Soochow University/Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, R2306, Bldg402, 199 Renai Road, Suzhou Industrial Park, Suzhou, Jiangsu Province, China 215123. Tel: +86-512-65882637; Fax: +86-512-65884830; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 24, pp. 9-15, 2016
0965-0407/16 $90.00
+ .00
DOI: http://dx.doi.org/10.3727/096504016X14570992647168
E-ISSN 1555-3906
Copyright
© 2016 Cognizant, LLC. 
Printed in the USA. All rights reserved

miR-1908 Overexpression Inhibits Proliferation, Changing Akt Activity and p53 Expression in Hypoxic NSCLC Cells

Yuefeng Ma,* Jie Feng,† Xin Xing,‡ Bin Zhou,* Shaomin Li,* Wei Zhang,* Jiantao Jiang,* Jin Zhang,* Zhe Qiao,* Liangzhang Sun,* Zhenchuan Ma,* and Ranran Kong*

*Department of Thoracic Surgery, the Second Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, Shaanxi, China
†Department of Nephrology, the First Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, Shaanxi, China
‡Department of Health Care for Cadres, the Second Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, Shaanxi, China

The ribosomal protein (RP)–p53 pathway has been shown to play a key role in apoptosis and senescence of cancer cells. miR-1908 is a newly found miRNA that was reported to have prognostic potential in melanoma. However, its role and mechanism in the progression of non-small cell lung cancer (NSCLC) are largely unknown. In this study, we found that expression of miR-1908 was significantly downregulated in human NSCLC cell lines, including SK-MES-1, A549, and NCI-H460. Then the role of miR-1908 in NSCLC cell proliferation was explored. The miR-1908 mimic was transfected into NSCLC cell lines, and their proliferation was detected. MTT and Cell Titer-Blue H analyses showed that the cell proliferation was notably reduced by the miR-1908 mimic transfection. Moreover, we found the RP–p53 pathway was activated by miR-1908 mimic. Moreover, the miR-1908 inhibitor transfection had a completely opposite effect on the NSCLC cell proliferation than that of miR-1908 mimic. To explore the underlying mechanism of that, TargetScan bioinformatics server and 3
-UTR luciferase reporter assay were applied to identify the targets of miR-1908. Our results showed that AKT1 substrate 1 (AKT1S1), a newly proven suppressor of the RP–p53 pathway, was a target of miR-1908, suggesting a probable mechanism for miR-191 suppressing NSCLC cell proliferation. Our findings provide a novel molecular target for the regulation of NSCLC cell proliferation.

Key words: Non-small cell lung cancer (NSCLC); miR-1908; AKT1 substrate 1 (AKT1S1); Ribosomal protein (RP)–p53 pathway; Cell proliferation

Address correspondence to Ranran Kong, Department of Thoracic Surgery, the Second Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, Shaanxi 710004, China. Tel: +86-029-87679556; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 24, pp. 17-23, 2016
0965-0407/16 $90.00
+ .00
DOI: http://dx.doi.org/10.3727/096504016X14570992647203
E-ISSN 1555-3906
Copyright
© 2016 Cognizant, LLC. 
Printed in the USA. All rights reserved

Overexpression of SASH1 Inhibits TGF-β1-Induced EMT in Gastric Cancer Cells

Wei Zong,* Chen Yu,† Ping Wang,* and Lei Dong‡

*Department of Gastroenterology, Shaanxi Provincial People’s Hospital, the Third Affiliated Hospital, College of Medicine, Xi’an Jiaotong University, Xi’an, China
†Department of Dermatology, Xijing Hospital, the Fourth Military Medical University, Xi’an, China
‡Department of Gastroenterology, the Second Affiliated Hospital, College of Medicine, Xi’an Jiaotong University, Xi’an, China

The epithelial–mesenchymal transition (EMT) is considered to be one of the critical steps in gastric cancer cell invasion and metastasis. SAM- and SH3-domain containing 1 (SASH1), a member of the SLY family of signal adapter proteins, is a candidate for tumor suppression in several cancers. However, the biological role of SASH1 in gastric cancer remains largely unknown. Therefore, the purpose of this study was to investigate the impact of SASH1 on the biological behavior of gastric cancer cells treated with transforming growth factor (TGF)-
β1. In the current study, we provide evidence that SASH1 was lowly expressed in human gastric cancer cells, and TGF-β1 also inhibited the expression of SASH1 in TSGH cells. We found that SASH1 inhibited TGF-β1-mediated EMT in TSGH cells, as well as cell migration and invasion. Furthermore, SASH1 obviously inhibited the phosphorylation of PI3K and Akt in TGF-β1-stimulated TSGH cells. In summary, our study is the first to show that overexpression of SASH1 inhibits TGF-β1-induced EMT in gastric cancer cells through the PI3K/Akt signaling pathway. These results suggest that SASH1 may be a potential therapeutic target for the treatment of gastric cancer.

Key words: SAM- and SH3-domain containing 1 (SASH1); Gastric cancer; Epithelial–mesenchymal transition (EMT)

Address correspondence to Wei Zong, Department of Gastroenterology, Shaanxi Provincial People’s Hospital, No. 256 West Youyi Road, Xi’an 710068, China. Tel: +86-029-85251331; Fax: +86-029-85236987; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 24, pp. 25-32, 2016
0965-0407/16 $90.00
+ .00
DOI: http://dx.doi.org/10.3727/096504016X14575597858609
E-ISSN 1555-3906
Copyright
© 2016 Cognizant, LLC. 
Printed in the USA. All rights reserved

Overexpression of SASH1 Inhibits the Proliferation, Invasion, and EMT in Hepatocarcinoma Cells

Ping He,* Hong-xia Zhang,† Chang-yu Sun,* Chun-yong Chen,‡ and He-qing Jiang*

*Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
†Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China
‡Zhengzhou Center for Disease Control and Prevention, Zhengzhou, China

The SASH1 (SAM- and SH3-domain containing 1) gene, a member of the SLY (SH3 domain containing expressed in lymphocytes) family of signal adapter proteins, has been implicated in tumorigenesis of many types of cancers. However, the role and mechanism of SASH1 in the invasion and metastasis of hepatocarcinoma are largely unknown. In this study, we investigated the role and mechanism of SASH1 in the invasion and metastasis of hepatocarcinoma. Our results showed that SASH1 was lowly expressed in hepatocarcinoma cell lines. The in vitro experiments showed that overexpression of SASH1 inhibited the proliferation and migration/invasion of hepatocarcinoma cells, as well as the epithelial–mesenchymal transition (EMT) progress. Furthermore, overexpression of SASH1 suppressed the expression of Shh as well as SmoPtc, and Gli-1 in hepatocarcinoma cells. Taken together, these results suggest that overexpression of SASH1 inhibited the proliferation and invasion of hepatocarcinomacells through the inactivation of Shh signaling pathway. Therefore, these findings reveal that SASH1 may be a potential therapeutic target for the treatment of hepatocarcinoma.

Key words: SAM- and SH3-domain containing 1 (SASH1); Hepatocarcinoma; Invasion; Epithelial–mesenchymal transition (EMT)

Address correspondence to Chang-yu Sun, Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China. Tel: +86-0371-67966261; Fax: +86-0371-67966261; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 24, pp. 33-39, 2016
0965-0407/16 $90.00
+ .00
DOI: http://dx.doi.org/10.3727/096504016X14575597858654
E-ISSN 1555-3906
Copyright
© 2016 Cognizant, LLC. 
Printed in the USA. All rights reserved

HPIP Silencing Prevents Epithelial–Mesenchymal Transition Induced by TGF-β1 in Human Ovarian Cancer Cells

Guo-ying Zhang,1 Ai-hua Liu,1 Guo-min Li, and Jian-rong Wang

Department of Obstetrics and Gynecology, Dongying People’s Hospital, Dongying, China

Hematopoietic pre-B-cell leukemia transcription factor (PBX)-interacting protein (HPIP/PBXIP1) is a nucleocytoplasmic shuttling protein, and its expression is associated with cancer aggressiveness. However, the role of HPIP in ovarian cancer is still unclear. Here, we aimed to clarify the role of HPIP in epithelial–mesenchymal transition (EMT) process of ovarian cancer cells, stimulated by transforming growth factor (TGF)-
β1. In this study, we found that HPIP was highly expressed in ovarian cancer cells, and TGF-β1 treatment induced HPIP expression in ovarian cancer cells. In addition, knockdown of HPIP suppressed TGF-β1-induced EMT and migration/invasion in ovarian cancer cells. Moreover, knockdown of HPIP significantly blocked the phosphorylated pattern of both PI3K and Akt induced by TGF-β1 in SKOV3 cells. In conclusion, the present study showed that HPIP silencing might prevent TGF-β1-induced EMT in ovarian cancer cells. Thus, HPIP may be a potential therapeutic target for the treatment of ovarian cancer.

Key words: HPIP; Ovarian cancer; Epithelial–mesenchymal transition (EMT); Transforming growth factor (TGF)-β1

1These authors provided equal contribution to this work.
Address correspondence to Jian-rong Wang, Department of Obstetrics and Gynecology, Dongying People’s Hospital, No. 317, Dongcheng South Road, Dongying 257091, China. Tel: +86-0546-8331577; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it



Oncology Research, Vol. 24, pp. 41-53, 2016
0965-0407/16 $90.00
+ .00
DOI: http://dx.doi.org/10.3727/096504016X14576297492418
E-ISSN 1555-3906
Copyright
© 2016 Cognizant, LLC. 
Printed in the USA. All rights reserved

PDGFRA and KIT Mutation Status and Its Association With Clinicopathological Properties, Including DOG1

Yasemin Baskin,*†‡ Gizem Calibasi Kocal,‡§ Betul Bolat Kucukzeybek,¶ Mahdi Akbarpour,# Nurcin Kayacik,** Ozgul Sagol,†† Hulya Ellidokuz,†‡‡ and Ilhan Oztop§§

*Institute of Oncology, Department of Basic Oncology, Dokuz Eylul University, Izmir, Turkey
†Faculty of Medicine, Department of Medical Informatics and Biostatistics, Dokuz Eylul University, Izmir, Turkey
‡Personalized Medicine and Pharmacogenomics/Genomics Research Centre-BIFAGEM, Dokuz Eylul University, Izmir, Turkey
§Institute of Health Sciences, Department of Basic Oncology, Dokuz Eylul University, Izmir, Turkey
¶Ataturk Training and Research Hospital, Department of Pathology, Izmir Katip Celebi University, Izmir, Turkey
#German Cancer Research Center, Division of Translational Oncology, Heidelberg, Germany
**Molecular Oncology Laboratory, Dokuz Eylul University Hospital, Izmir, Turkey
††Faculty of Medicine, Department of Pathology, Dokuz Eylul University, Izmir, Turkey
‡‡Institute of Oncology, Department of Preventive Oncology, Dokuz Eylul University, Izmir, Turkey
§§Faculty of Medicine, Department of Medical Oncology, Dokuz Eylul University, Izmir, Turkey

Most of the gastrointestinal stromal tumors (GISTs) have gain-of-function mutations in the
KIT gene, which can be used as a prognostic marker for the biological behavior of tumors, predictive marker for the response of tyrosine kinase inhibitors, and diagnostic marker. Researchers have focused on PDGFRA mutations because of both their prognostic and predictive potential and DOG1 positivity for diagnosis on GISTs. The aim of this study is to investigate the effect DOG1, PDGFRA, and KIT mutations on the prediction of the outcome for GIST management. Polymerase chain reaction was performed for KIT gene exons 9, 11, 13, and 17 and PDGFRA gene exons 12 and 18 with the genomic DNA of 46 GIST patients, and amplicons were sequenced in both directions. Immunocytochemical stainings were done by using primary antibodies. Molecular analysis revealed that the KIT mutation was observed in 63% of all cases, while the PDGFRA mutation was observed in 23.9% of cases. Significant relationships were found between age and KIT mutation, tumor location and KIT mutations, and tumor location and PDGFRA mutations (p 0.05). DOG1 positivity was detected in 65.2% of all GISTs and DOG1-positive cells had a higher KIT mutation ratio than DOG1-negative cells (p 0.05). KIT gene exon 11 mutations in DOG1-positive cells was higher than DOG1-negative cells (p 0.05). Conversely, KIT gene exon 13 mutations were higher in DOG1-negative cells than DOG1-positive cells (p 0.05). In this study,KIT mutation frequency was found similar with the European population; conversely, PDGFRA mutation frequency was similar with an Asian-Chinese-based study. KIT/PDGFRA mutations and tumor location can be used for the prediction of tumor behavior and the management of disease in GISTs. DOG1 positivity might be a candidate marker to support KIT and PDGFRA mutations, due to the higher DOG1 positivity in KIT exon 11 mutant and stomach- and small intestine-localized GISTs.

Key words: Gastrointestinal stromal tumors (GISTs); KIT gene; PDGFRA gene; Mutations; DOG1

Address correspondence to Yasemin Baskin, M.D., Ph.D., Institute of Oncology, Department of Basic Oncology, Dokuz Eylul University Medical School Campus, 35350, Inciraltı-Izmir, Turkey. Tel: +90 (232) 412 5890; Fax: +90 (232) 278 9495; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 24, pp. 55-64, 2016
0965-0407/16 $90.00
+ .00
DOI: http://dx.doi.org/10.3727/096504016X14586627440192
E-ISSN 1555-3906
Copyright
© 2016 Cognizant, LLC. 
Printed in the USA. All rights reserved

2-Deoxy-D-glucose Suppresses the In Vivo Antitumor Efficacy of Erlotinib in Head and Neck Squamous Cell Carcinoma Cells

Arya Sobhakumari,*1 Kevin P. Orcutt,†‡1 Laurie Love-Homan,§ Christopher E. Kowalski,†‡ Arlene D. Parsons,† C. Michael Knudson,†‡§¶ and Andrean L. Simons*†‡§¶

*Interdisciplinary Human Toxicology Program, The University of Iowa, Iowa City, IA, USA
†Department of Radiation Oncology, The University of Iowa, Iowa City, IA, USA
‡Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, USA
§Department of Pathology, The University of Iowa, Iowa City, IA, USA
¶Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, USA

Poor tumor response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a significant challenge for effective treatment of head and neck squamous cell carcinoma (HNSCC). Therefore, strategies that may increase tumor response to EGFR TKIs are warranted in order to improve HNSCC patient treatment and overall survival. HNSCC tumors are highly glycolytic, and increased EGFR signaling has been found to promote glucose metabolism through various mechanisms. We have previously shown that inhibition of glycolysis with 2-deoxy-D-glucose (2DG) significantly enhanced the antitumor effects of cisplatin and radiation, which are commonly used to treat HNSCC. The goal of the current studies is to determine if 2DG will enhance the antitumor activity of the EGFR TKI erlotinib in HNSCC. Erlotinib transiently suppressed glucose consumption accompanied by alterations in pyruvate kinase M2 (PKM2) expression. 2DG enhanced the cytotoxic effect of erlotinib in vitro but reversed the antitumor effect of erlotinib in vivo. 2DG altered the N-glycosylation status of EGFR and induced the endoplasmic reticulum (ER) stress markers CHOP and BiP in vitro. Additionally, the effects of 2DG + erlotinib on cytotoxicity and ER stress in vitro were reversed by mannose but not glucose or antioxidant enzymes. Lastly, the protective effect of 2DG on erlotinib-induced cytotoxicity in vivo was reversed by chloroquine. Altogether, 2DG suppressed the antitumor efficacy of erlotinib in a HNSCC xenograft mouse model, which may be due to increased cytoprotective autophagy mediated by ER stress activation.

Key words: Epidermal growth factor receptor (EGFR); Head and neck squamous cell carcinoma (HNSCC); Erlotinib; 2-Deoxy-D-glucose (2DG); Endoplasmic reticulum (ER) stress; Autophagy

1These authors provided equal contribution to this work.
Address correspondence to Andrean L. Simons, Ph.D., Assistant Professor, Department of Pathology, University of Iowa, 1161 Medical Laboratories, 500 Newton Road, Iowa City, IA 52242, USA. Tel: 319-384-4450; Fax: 319-335-8453; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 24, pp. 65-72, 2016
0965-0407/16 $90.00
+ .00
DOI: http://dx.doi.org/10.3727/096504016X14587366983838
E-ISSN 1555-3906
Copyright
© 2016 Cognizant, LLC. 
Printed in the USA. All rights reserved

ABT-737, a Bcl-2 Selective Inhibitor, and Chloroquine Synergistically Kill Renal Cancer Cells

Pei Yin,*1 Jinpeng Jia,†1 Jijun Li,* Yan Song,* Yiyan Zhang,* and Fengkun Chen*

*Department of Nephrology, First Affiliated Hospital of Chinese PLA General Hospital, Beijing, China
†Department of Orthopaedics, General Hospital of Chinese People’s Liberation Army, Beijing, China

Renal cell carcinoma (RCC) is the most common malignancy in the kidney in the world, and the 5-year overall survival for patients remains poor due to the lack of effective treatment strategies. Although ABT-737, as a Bcl-2/Bcl-xL inhibitor, has recently emerged as a novel cancer therapeutic reagent, apoptosis induced by ABT-737 is often blocked in several types of cancer cells. This study investigated whether the combination of the small-molecule BH3 mimetic ABT-737 and the lysosome inhibitor chloroquine was an effective strategy for treating renal cancer cells. We found that the combination of ABT-737 and chloroquine synergistically decreased cell viability when compared to treatment with either single reagent. Cell apoptosis induced by a combined treatment was markedly inhibited by the caspase inhibitors z-DEVD-FMK and z-VAD-FMK. It was also inhibited by cathepsin inhibitor E-64 and CTSI (cathepsin inhibitor), which suggested that apoptosis was dependent on the cascade of caspase activation and cathepsins released from lysosomes. Furthermore, we found that ABT-737 could increase the cell level of ROS, which triggers cathepsin-mediated cell death and augments the role of chloroquine in cell death. So the combination of ABT-737 and chloroquine was an effective strategy for the treatment of renal cancer cells, and this combined strategy may widen the therapeutic window of ABT-737 and chloroquine as well as enhance the clinical efficacy of synergistic drug combinations.

Key words: ABT-737; Chloroquine; Renal cancer; Apoptosis; Combination treatment

1These authors provided equal contribution to this work.
Address correspondence to Jijun Li, Department of Nephrology, First Affiliated Hospital of Chinese PLA General Hospital, No. 51 Fucheng Road, Beijing, China 100037. Tel: +86-10-66848161; Fax: +86-10-66848161; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it