Oncology Research 27(6) Abstracts

Return to Oncology Research>

Oncology Research, Vol. 27, pp. 629-634, 2019
0965-0407/19 $90.00 +.00
DOI: https://doi.org/10.3727/096504018X
15228018559434
E-ISSN 1555-3906
Copyright ©2019 Cognizant, LLC.
Printed in the USA. All rights reserved.

Kaempferol Suppresses Proliferation and Induces Cell Cycle Arrest, Apoptosis, and DNA Damage in Breast Cancer Cells

Li Zhu* and Lijun Xue

*Department of Medical Laboratory, Shanghai Second People’s Hospital, Shanghai, P.R. China
†Madonna University, Livonia, MI, USA

Kaempferol is a flavonoid that has been extensively investigated owing to its antitumor effects. Nevertheless, little is known about its underlying mechanisms of action. We aimed to explore the role of kaempferol in breast cancer (BC), and thus we investigated how kaempferol suppresses the growth of BC cells. The cells were treated with kaempferol, and the effects on multiple cancer-associated pathways were evaluated. The MTS assay was used to study the cell growth inhibition induced by kaempferol. The cell cycle was analyzed by flow cytometry. Western blotting was used to analyze cellular apoptosis and DNA damage. We found that the proliferation of the triple-negative BC (TNBC) MDA-MB-231 cells was suppressed effectively by kaempferol. Interestingly, the suppressive effect of kaempferol on cell proliferation was stronger in MDA-MB-231 cells than in the estrogen receptor-positive BT474 cell line. Furthermore, after the treatment with kaempferol for 48 h, the population of cells in the G1
phase was significantly reduced, from 85.48% to 51.35%, and the population of cells in the G2 phase increased markedly from 9.27% to 37.5%, which indicated that kaempferol contributed to the induction of G2/M arrest. Kaempferol also induced apoptosis and DNA damage in MDA-MB-231 cells. Kaempferol increased the expression levels of gH2AX, cleaved caspase 9, cleaved caspase 3, and p-ATM compared to those of the control group. Collectively, these results showed that kaempferol may be a potential drug for the effective treatment of TNBC.

Key words: Kaempferol; Cell proliferation; Cell cycle; Apoptosis; DNA damage; Breast cancer (BC)

Address correspondence to Lijun Xue, Madonna University, No. 36600 Schoolcraft Road, Livonia, MI 48150-1176, USA. Tel: +86-734-432-5703; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 27, pp. 635-641, 2019
0965-0407/19 $90.00 +.00
DOI: https://doi.org/10.3727/096504018X
15288447760357
E-ISSN 1555-3906
Copyright ©2019 Cognizant, LLC.
Printed in the USA. All rights reserved.

Apatinib Plus Chemotherapy Shows Clinical Activity in Advanced NSCLC: A Retrospective Study

Jing Tang,*1 Xu Yong Li,†1 Jing Bo Liang,‡ De Wu,§ Li Peng,¶ and Xiaobing Li¶

*Department of Lymphoma in Hubei Cancer Hospital, Wuhan City, Hubei Province, P.R. China
†Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei Province, P.R. China
‡Department of People’s Hospital of Yicheng, Xiang yang City, Hubei Province, P.R. China
§Centre of Molecular Diagnosis in Hubei Cancer Hospital, Wuhan City, Hubei Province, P.R. China
¶Department of 1st Division of Thoracic Tumor in Hubei Cancer Hospital, Wuhan City, Hubei Province, P.R. China

Apatinib is an oral TKI with antiangiogenic properties, and it is currently approved for the treatment of advanced gastric cancer in China. This agent has also been tested in other human solid tumors, including non-small cell lung cancer (NSCLC). Since the combination of chemotherapy and an antiangiogenic agent has been shown to be a feasible strategy in NSCLC, it is conceivable that a similar approach combining apatinib with chemotherapy may yield clinical activity. With this in mind, we investigated the efficiency of apatinib in combination with pemetrexed or docetaxel in advanced NSCLC. We treated a total of 20 patients with metastatic NSCLC adenocarcinoma with apatinib in combination with either pemetrexed or docetaxel from January 2016 to March 2017. The performance status of these patients was 0 or 1. All of these patients had been previously treated with two or more lines of treatment and had experienced disease progression prior to study enrollment. The overall objective response rate (ORR) was 30%, with 6 patients who had partial response (PR), 10 patients who had stable disease (SD), and 4 patients who had progressive disease (PD). The main adverse events were skin rash, hypertension, palmar–plantar erythrodysesthesia syndrome, diarrhea, and fatigue. Nearly 30% of patients required interruption of treatment as a result of toxicity. Our study demonstrated that apatinib combined with systemic cytotoxic chemotherapy has clinical efficacy in patients with disease-refractory metastatic NSCLC and provides evidence for further studies investigating apatinib-based combination regimens.

Key words: Antiangiogenesis therapy; Apatinib; Non-small cell lung cancer (NSCLC); Cytotoxic chemotherapy; Adenocarcinoma

1These authors provided equal contribution to this work.
Address correspondence to Xiaobing Li, Department of 1st Division of Thoracic Tumor in Hubei Cancer Hospital, #116 Zuodaoquan South Road, Hongshan District, Wuhan City 430079, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 27, pp. 643-651, 2019
0965-0407/19 $90.00 +.00
DOI: https://doi.org/10.3727/096504018X
15415906335771
E-ISSN 1555-3906
Copyright ©2019 Cognizant, LLC.
Printed in the USA. All rights reserved.

Heme Oxygenase-1 Inhibits Tumor Metastasis Mediated by Notch1 Pathway in Murine Mammary Carcinoma

Qiang Li,*†1 Qi Liu,*1 Wanpeng Cheng,* Huiyan Wei,* Wenqian Jiang,* Fang E,* Yuan Yu,* Jianfeng Jin,* and Chaoxia Zou*‡

*Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, P.R. China
†Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, P.R. China
‡Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medicine Sciences, Harbin, P.R. China

Heme oxygenase-1 (HO-1) plays an important role in the progression of several malignancies including breast cancer. However, its role in breast cancer metastasis is still ambiguous. In this study, we observed the effect of HO-1 on mouse mammary carcinoma metastasis using the in vivo tumor metastasis model. Our results revealed that overexpression of HO-1 strongly inhibits the lung metastasis of 4T1 cells. In in vitro analysis, associated indices for epithelial–mesenchymal transition (EMT), migration, and proliferation of 4T1 cells were evaluated. The results show that HO-1 inhibits EMT, migration, and proliferation of 4T1 cells. In addition, the Notch1/Slug pathway is found to mediate an antimetastasis role of HO-1 in mouse mammary carcinoma. In conclusion, since HO-1/Notch1/Slug axis plays an important role in breast cancer metastasis, induction of HO-1 could be used as a potential therapeutic strategy for breast cancer treatment.

Key words: Murine mammary carcinoma; Heme oxygenase-1 (HO-1); Tumor metastasis; Epithelial–mesenchymal transition (EMT); Notch1 signaling

1These authors provided equal contribution to this work.
Address correspondence to Chaoxia Zou, Department of Biochemistry and Molecular Biology, Harbin Medical University, 157 Baojian Road, Nangang, Harbin, Heilongjiang, P.R. China. Tel/Fax: +86 451 8708 6131; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 27, pp. 653-661, 2019
0965-0407/19 $90.00 +.00
DOI: https://doi.org/10.3727/096504018X
15420748671075
E-ISSN 1555-3906
Copyright ©2019 Cognizant, LLC.
Printed in the USA. All rights reserved.

Silencing of lncRNA AFAP1-AS1 Inhibits Cell Growth and Metastasis in Clear Cell Renal Cell Carcinoma

Zhongyi Mu,*†1 Dan Dong,*1 Ning Wei,‡§ Mingli Sun,¶ Wei Wang,* Yue Shao,* Jian Gao,* Ping Yin,* and Chenghai Zhao*

*Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, P.R. China
†Department of Urology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, P.R. China
‡Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
§Cancer Therapeutics Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
¶Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, P.R. China

The lncRNA AFAP1-AS1, oriented from an antisense direction to the protein-coding gene AFAP1 in the opposite strand, was upregulated in a variety of tumors and associated with poor prognosis, including lung cancer, breast cancer, ovarian cancer, and so on. However, the biological role of AFAP1-AS1 in clear cell renal cell carcinoma (ccRCC) is still unknown. We observed that AFAP1-AS1 expression was significantly upregulated in ccRCC tissues and that patients with high-level expression of AFAP1-AS1 had a shorter overall survival. Knockdown of AFAP1-AS1 markedly suppressed the progression of proliferation, invasion, migration, and EMT in ccRCC cells. Downregulation of AFAP1-AS1 resulted in an increase in E-cadherin and a decrease in vimentin. Noticeably, we found that PTEN has a negative correlation with the lncRNA AFAP1-AS1 expression. Further studies verified that PTEN deficiency effectively attenuated the ability of AFAP1-AS1 in promoting ccRCC cell proliferation, invasion, migration, and EMT. Moreover, the similar biological response of silencing AFAP1-AS1 was observed in our ccRCC mice model. Knockdown of AFAP1-AS1 evidently suppressed tumor growth. Taken together, our results provide the evidences that silencing of AFAP1-AS1 inhibits cell proliferation, EMT, and metastasis through PTEN-dependent signaling, and our findings elucidate a novel potential therapeutic target or biomarker for the treatment of ccRCC.

Key words: Long noncoding RNAs (lncRNAs); AFAP1-AS1; Clear cell renal cell carcinoma (ccRCC); Metastasis; Phosphatase and tensin homolog (PTEN)

1These authors provided equal contribution to this work.
Address correspondence to Chenghai Zhao, Department of Pathophysiology, College of Basic Medical Science, China Medical University, 77 Puhe Rd, Shenbei Xinqu, Shenyang, Liaoning Province, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 27, pp. 663-672, 2019
0965-0407/19 $90.00 +.00
DOI: https://doi.org/10.3727/096504018X
15420741307616
E-ISSN 1555-3906
Copyright ©2019 Cognizant, LLC.
Printed in the USA. All rights reserved.

The Interaction Between lncRNA SNHG1 and miR-140 in Regulating Growth and Tumorigenesis via the TLR4/NF-κB Pathway in Cholangiocarcinoma

Zhen Li,*1 Xin Li,*1 Xiao Du,† Henghui Zhang,† Zhengyang Wu,* Kewei Ren,* and Xinwei Han*

*Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
†Beijing Genecast Biotechnology Co., Beijing, P.R. China

Cholangiocarcinoma (CCA) is the second most common primary hepatobiliary carcinoma. The long noncoding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) has been reported to contribute to the progression of multiple cancers. Nonetheless, the functions and hidden mechanism of SNHG1 remain unclear in CCA. In this study, the SNHG1 levels were boosted in CCA cell lines, and knockdown of SNHG1 repressed CCA cell proliferation and invasion in vitro. The data also demonstrated that miR-140 could act as a target of SNHG1 in CCA and inhibited CCA cell proliferation and invasion, whereas the inhibition effects were relieved by overexpression of SNHG1. In addition, Toll-like receptor 4 (TLR4), an NF-
κB-activating signal, was identified to be a target of miR-140. SNHG1, as a competing endogenous RNA (ceRNA) for miR-140, enhanced TLR4 expression and activated NF-κB signaling, thereby regulating growth and tumorigenesis in CCA. Animal experiments further confirmed this conclusion. Collectively, these findings not only uncovered a key role of SNHG1/miR-140/TLR4/NF-κB signaling axis in CCA tumorigenesis and progression but also denoted the probable utilization of SNHG1 as a therapeutic target for CCA.

Key words: Cholangiocarcinoma (CCA); Long noncoding RNAs (lncRNAs) SNHG1; miR-140; Toll-like receptor 4 (TLR4); NF-κB signaling

1These authors provided equal contribution to this work.
Address correspondence to Zhen Li, Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450052, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Xinwei Han, Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450052, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 27, pp. 673-680, 2019
0965-0407/19 $90.00 +.00
DOI: https://doi.org/10.3727/096504018X
15426261956343
E-ISSN 1555-3906
Copyright ©2019 Cognizant, LLC.
Printed in the USA. All rights reserved.

Knockdown of IARS2 Inhibited Proliferation of Acute Myeloid Leukemia Cells by Regulating p53/p21/PCNA/eIF4E Pathway

Hong Li,*1 Yaning Tian,*1 Xiang Li,* Bin Wang,† Dongzhi Zhai,* Yingying Bai,* Changhu Dong,* and Xu Chao*‡

*The Second Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, P.R. China
†The College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, P.R. China
‡The College of Preclinical Sciences, Shaanxi University of Chinese Medicine, Xianyang, P.R. China

IARS2 encodes mitochondrial isoleucine-tRNA synthetase, which mutation may cause multiple diseases. However, the biological function of IARS2 on acute myeloid leukemia (AML) has not yet been identified. In the present study, qRT-PCR was used to determine the expression of IARS2 in K562, THP1, and HL-60 leukemia cells. Additionally the mRNA levels of IARS2 in CD34 cells and AML cells obtained from patients were detected by qRT-PCR. IARS2-shRNA lentiviral vector was established and used to infect acute myeloid leukemia HL-60 cells. qRT-PCR and Western blot analysis were employed to assess the knockdown effect of IARS2. The proliferation rate and cell cycle phase of HL-60 cells after IARS2 knockdown were evaluated by CCK-8 assay and flow cytometry. The PathScan Antibody Array was used to determine the expression of cell cycle-related proteins in HL-60 cells after IARS2 knockdown. The expression of proliferation-related proteins in HL-60 cells after IARS2 knockdown was determined by Western blot analysis. Results showed that IARS2 expression was stable and much higher in HL-60, THP-1, and K562 leukemia cells and AML cells obtained from patients than that of human CD34 cells. Compared with cells of the shCtrlgroup, IARS2 was markedly knocked down in cells that were transfected with lentivirus encoding shRNA of IARS2 in HL-60 cells (
p < 0.05). IARS2 knockdown significantly inhibited the proliferation and induced cycle arrest at the G1 phase in HL-60 cells. Additionally IARS2 knockdown significantly increased the expression of p53 and p21, and decreased the expression of PCNA and eIF4E in HL-60 cells. In conclusion, IARS2 knockdown can inhibit acute myeloid leukemia HL-60 cell proliferation and cause cell cycle arrest at the G1 phase by regulating the p53/p21/PCNA/eIF4E pathways.

Key words: Acute myeloid leukemia (AML); IARS2; Proliferation

1These authors provided equal contribution to this work.
Address correspondence to Xu Chao, The Second Affiliated Hospital of Shaanxi University of Chinese Medicine, Weiyang West Road, XianyangP.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 27, pp. 681-690, 2019
0965-0407/19 $90.00 +.00
DOI: https://doi.org/10.3727/096504018X
15424939990246
E-ISSN 1555-3906
Copyright ©2019 Cognizant, LLC.
Printed in the USA. All rights reserved.

Knockdown of lncRNA PVT1 Inhibits Glioma Progression by Regulating miR-424 Expression

Yanjie Han,*1 Xinxin Li,*1 Fei He,†1 Jiliang Yan,* Chunyan Ma,* Xiaoli Zheng,‡ Jinli Zhang,* Donghui Zhang,* Cuiping Meng,* Zhen Zhang,* and Xinying Ji§

*Clinical Laboratory and Functional Laboratory, Kaifeng Central Hospital, Kaifeng, Henan, P.R. China
†Department of Cardiothoracic Surgery, Huai-He Hospital, College of Medicine, Henan University, Kaifeng, Henan, P.R. China
‡Hospital Infection Control Office, First Affiliated Hospital of Henan University, Kaifeng, Henan, P.R. China
§Henan International Joint Laboratory of Nuclear Protein Regulation, Henan University College of Medicine, Kaifeng, Henan, P.R. China

Plasmacytoma variability translocation 1 (PVT1), an oncogene, has been reported to be highly expressed in many tumors, including human glioma, gastric cancer, and non-small cell lung cancer. Functionally, it could also regulate the development of tumor cells. However, its specific roles and pathogenesis in human gliomas are still not clear. This study investigated the function and mechanism of PVT1 knockdown in the proliferation and malignant transformation of human gliomas. We first examined the expression levels of PVT1 and miR-424 in human glioma tissues and cell lines. We also used gene manipulation techniques to explore the effects of PVT1 knockdown on cell viability, migration, invasion, and miR-424. We found that PVT1 knockdown effectively inhibited cell viability, migration, and invasion of human glioma cells and increased miR-424 expression. Based on the negative correlation between PVT1 and miR-424, we then confirmed the direct interaction between PVT1 and miR-424 using RNA immunoprecipitation (RIP) and luciferase reporter assays. Further, we established a xenograft nude mouse model to determine the role and mechanism of PVT1 on tumor growth in vivo. In addition, PVT1 knockdown was shown to promote miR-424 in vivo. In summary, the present study demonstrated that PVT1 knockdown could negatively regulate miR-424 to inhibit human glioma cell activity, migration, and invasiveness. PVT1 knockdown could negatively regulate miR-424 to inhibit cellular activity, migration, and invasiveness in human gliomas, which explained the oncogenic mechanism of PVT1 in human gliomas. It also suggested that PVT1 might be a novel therapeutic target for human gliomas.

Key words: PVT1; miR-424; Human glioma

1Joint first authorship.
Address correspondence to Dr. Yanjie Han, Clinical Laboratory, Kaifeng Central Hospital, 85 Hedao Street, Kaifeng, Henan 475000, P.R. China. Tel: +8603715672695; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Xin-Ying Ji, Henan International Joint Laboratory of Nuclear Protein Regulation, Henan University College of Medicine, Kaifeng, Henan 475004, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 27, pp. 691-701, 2019
0965-0407/19 $90.00 +.00
DOI: https://doi.org/10.3727/096504018X
15426763753594
E-ISSN 1555-3906
Copyright ©2019 Cognizant, LLC.
Printed in the USA. All rights reserved.

MicroRNA-101 Targets CXCL12-Mediated Akt and Snail Signaling Pathways to Inhibit Cellular Proliferation and Invasion in Papillary Thyroid Carcinoma

Fang Chen,* Dongqiang Yang,† Yuhua Ru,‡ Shan Cao,* and Aishe Gao*

*Department of Pathophysiology, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, P.R. China
†Department of Infectious Diseases, Henan Provincial People’s Hospital, Zhengzhou, Henan, P.R. China
‡Department of Medical Academy, Soochow University, Soochow, Jiangsu, P.R. China

Escalating evidence suggests that microRNA-101 (miR-101) is implicated in the development and progression of various cancers, including papillary thyroid carcinoma (PTC). However, the biological function and molecular mechanisms of miR-101 in PTC are still unclear. In this study, we demonstrated that miR-101 expression was significantly decreased in PTC tissues and cell lines. Clinically, a low level of miR-101 was positively associated with advanced histological stages and lymph node and distant metastases. The expression of CXCL12 was negatively correlated with miR-101 level in PTC. CXCL12 was validated as a direct target of miR-101 in PTC cells. Functional experiments proved that miR-101 markedly reduced the proliferation, apoptosis escape, migration, and invasion of PTC cells. Moreover, CXCL12 restoration rescued the suppressive effects of miR-101 on PTC cells by activating Akt- and EMT-associated signaling pathways. Overall, miR-101 exerts oncostatic effects on PTC by downregulating CXCL12 and repressing its downstream Akt and Snail signaling pathways, suggesting that miR-101/CXCL12/Akt or Snail axis may serve as a potential therapeutic target for PTC.

Key words: miR-101; Papillary thyroid carcinoma (PTC); CXCL12; Growth; Metastasis; Akt signaling

Address correspondence to Dongqiang Yang, M.D., Department of Infectious Diseases, Henan Provincial Peoples’ Hospital, No. 7 Weiwu Road, Zhengzhou, Henan 450003, P.R. China. Tel: +86-371-65587667; Fax: +86-371-65897628; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Aishe Gao, M.D., Department of Pathophysiology, Henan University of Traditional Chinese Medicine, No. 1 East Jinshui Road, Zhengzhou, Henan 450008, P.R. China. Tel: +86-371-65765555; Fax: +86-371-65765555; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 27, pp. 703-712, 2019
0965-0407/19 $90.00 +.00
DOI: https://doi.org/10.3727/096504018X
15426775024905
E-ISSN 1555-3906
Copyright ©2019 Cognizant, LLC.
Printed in the USA. All rights reserved.

miR-374a Inhibitor Enhances Etoposide-Induced Cytotoxicity Against Glioma Cells Through Upregulation of FOXO1

Wei Ni,*†‡ Lin Luo,*†‡ Ping Zuo,*†‡ Renping Li,*†‡ Xiaobing Xu,*†‡ Fan Wen,*†‡ and Dong Hu*†‡

*Department of Neurosurgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, P.R. China
†Department of Neurosurgery, Yunnan Cancer Hospital, Kunming, P.R. China
‡Department of Neurosurgery, Yunnan Cancer Center, Kunming, P.R. China

Glioma is a commonly diagnosed brain tumor that shows high mortality rate. Despite the great advancement of cancer therapy in recent years, chemotherapy is still an important approach for treatment of glioma. However, long-term chemotherapy usually causes serious side effects or complications. It is desirable to take strategies to enhance the efficacy of current chemotherapy. In the present study, we observed obvious upregulation of miR-374a in glioma cells. More importantly, we found that knockdown of miR-374a was able to enhance the etoposide-induced cytotoxicity against glioma cells. Mechanically, we demonstrated that FOXO1 was the target of miR-374a in glioma. Treatment with miR-374a inhibitor induced overexpression of FOXO1, and thus promoted the expression of Bim and Noxa. Since Bim and Noxa act as key proapoptotic proteins in mitochondrial apoptosis, miR-374a inhibitor was able to enhance the etoposide-induced apoptosis pathway in glioma.

Key words: Etoposide; miR-374a inhibitor; Glioma; FOXO1

Address correspondence to Lin Luo, Department of Neurosurgery, The Third Affiliated Hospital of Kunming Medical University, No. 519 Kunzhou Road, Xishan District, Kunming City, Yunnan Province 650118, P.R. China. Tel: +86087168178184; Fax: +86087167185730; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 27, pp. 713-727, 2019
0965-0407/19 $90.00 +.00
DOI: https://doi.org/10.3727/096504018X
15433161908259
E-ISSN 1555-3906
Copyright ©2019 Cognizant, LLC.
Printed in the USA. All rights reserved.

Extracellular S100A11 Plays a Critical Role in Spread of the Fibroblast Population in Pancreatic Cancers

Hitoshi Takamatsu,*1 Ken-ichi Yamamoto,*1 Nahoko Tomonobu,* Hitoshi Murata,* Yusuke Inoue,† Akira Yamauchi,‡ I Wayan Sumardika,*§ Youyi Chen,* Rie Kinoshita,* Masahiro Yamamura,¶ HideyoFujiwara,# Yosuke Mitsui,*,** Kota Araki,*†† Junichiro Futami,‡‡ Ken Saito,§§ Hidekazu Iioka,§§ I Made Winarsa Ruma,§ Endy Widya Putranto,¶ Masahiro Nishibori,## Eisaku Kondo,§§ Yasuhiko Yamamoto,*** Shinichi Toyooka,†† and Masakiyo Sakaguchi*

*Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
†Faculty of Science and Technology, Division of Molecular Science, Gunma University, Kiryu, Gunma, Japan
‡Department of Biochemistry, Kawasaki Medical School, Kurashiki, Okayama, Japan
§Faculty of Medicine, Udayana University, Denpasar, Bali, Indonesia
¶Department of Clinical Oncology, Kawasaki Medical School, Kurashiki, Okayama, Japan
#Department of Pathology, Kawasaki Medical School, Kurashiki, Okayama, Japan
**Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
††Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
‡‡Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan
§§Division of Molecular and Cellular Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
¶¶Department of Pediatrics, Dr. Sardjito Hospital/Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
##Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
***Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan

The fertile stroma in pancreatic ductal adenocarcinomas (PDACs) has been suspected to greatly contribute to PDAC progression. Since the main cell constituents of the stroma are fibroblasts, there is crosstalking(s) between PDAC cells and surrounding fibroblasts in the stroma, which induces a fibroblast proliferation burst. We have reported that several malignant cancer cells including PDAC cells secrete a pronounced level of S100A11, which in turn stimulates proliferation of cancer cells via the receptor for advanced glycation end products (RAGE) in an autocrine manner. Owing to the RAGE
+ expression in fibroblasts, the extracellular abundant S100A11 will affect adjacent fibroblasts. In this study, we investigated the significance of the paracrine axis of S100A11–RAGE in fibroblasts for their proliferation activity. In in vitro settings, extracellular S100A11 induced upregulation of fibroblast proliferation. Our mechanistic studies revealed that the induction is through RAGE–MyD88–mTOR–p70 S6 kinase upon S100A11 stimulation. The paracrine effect on fibroblasts is linked mainly to triggering growth but not cellular motility. Thus, the identified pathway might become a potential therapeutic target to suppress PDAC progression through preventing PDAC-associated fibroblast proliferation.

Key words: S100A11; Pancreatic cancer; Fibroblasts; RAGE; Cancer microenvironment

1These authors provided equal contribution to this work.
Address correspondence to Masakiyo Sakaguchi, Ph.D., Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama 700-8558, Japan. Tel: +81-86-235-7395; Fax: +81-86-235-7400; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 27, pp. 729-737, 2019
0965-0407/19 $90.00 +.00
DOI: https://doi.org/10.3727/096504018X
15443011011637
E-ISSN 1555-3906
Copyright ©2019 Cognizant, LLC.
Printed in the USA. All rights reserved.

Synergistic Efficacy of the Demethylation Agent Decitabine in Combination With the Protease Inhibitor Bortezomib for Treating Multiple Myeloma Through the Wnt/β-Catenin Pathway

Yulong Jin,* Li Xu,* Xiaodong Wu,Juan Feng,* Mimi Shu,* Hongtao Gu,* Guangxun Gao,* Jinyi Zhang,Baoxia Dong,* and Xiequn Chen*

*Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, P.R. China
†Department of Cell Biology, Fourth Military Medical University, Xi’an, Shaanxi, P.R. China
‡Department of School of Life Sciences, Jinzhou Medical University, Jinzhou, Liaoning, P.R. China

Multiple myeloma (MM) is a hematopoietic malignancy characterized by the clonal proliferation of antibody-secreting plasma cells. Bortezomib (BZM), the first FDA-approved proteasome inhibitor, has significant antimyeloma activity and prolongs the median survival of MM patients. However, MM remains incurable predominantly due to acquired drug resistance and disease relapse.
β-Catenin, a key effector protein in the canonical Wnt signaling pathway, has been implicated in regulating myeloma cell sensitivity to BZM. Decitabine (DAC) is an epigenetic modulating agent that induces tumor suppressor gene reexpression based on its gene-specific DNA hypomethylation. DAC has been implicated in modulating Wnt/β-catenin signaling by promoting the demethylation of the Wnt/β-catenin antagonists sFRP and DKK. In this study, we report the effects of single reagent DAC therapy and DAC combined with BZM on β-catenin accumulation, myeloma cell survival, apoptosis, and treatment sensitivity. Our study proved that DAC demethylated and induced the reexpression of the Wnt antagonists sFRP3 and DKK1. DAC also reduced GSK3β (Ser9) phosphorylation and decreased b-catenin accumulation in the nucleus, which were induced by BZM. Thus, the transcription of cyclin D1, c-Myc, and LEF/TCF was reduced, which synergistically inhibited cell proliferation, enhanced BZM-induced apoptosis, and promoted BZM-induced cell cycle arrest in myeloma cells. In summary, these results indicated that DAC could synergistically enhance myeloma cell sensitivity to BZM at least partly by regulating Wnt/β-catenin signaling. Our results can be used to optimize therapeutic regimens for MM.

Key words: Multiple myeloma (MM); BortezomibDecitabineWnt/β-catenin pathway; Demethylation

Address correspondence to Xiequn Chen, Department of Hematology, Xijing Hospital, Fourth Military Medical University, No. 17 Changle West Road, Xi’an 710032, Shaanxi, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Baoxia Dong, Department of Hematology, XijingHospital, Fourth Military Medical University, Xi’an 710032, Shaanxi, P.R. China. Tel: +86 15619000099; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it