Oncology Research 26(3) Abstracts

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Oncology Research, Vol. 26, pp. 335-343, 2018
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X14907375885605
E-ISSN 1555-3906
Copyright ©2018 Cognizant, LLC.
Printed in the USA. All rights reserved.

Long Noncoding RNA LINC01133 Functions as an miR-422a Sponge to Aggravate the Tumorigenesis of Human Osteosarcoma

Hai-Feng Zeng,* Hai-Yan Qiu,† and Fa-Bo Feng‡

*Department of Plastic Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, P.R. China
†Department of Endocrinology, Hangzhou First People’s Hospital, Nanjing Medical University, Nanjing, P.R. China
‡Department of Orthopedics, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, P.R. China

Long noncoding RNAs (lncRNAs) have been verified to participate in various types of malignant tumors, including osteosarcoma (OS), which is the most common primary bone tumor with outstanding morbidity. Although an increasing number of lncRNAs have been reported to mediate the occurrence of OS, the potential mechanisms are still unclear. This study intends to uncover the mechanism by which lncRNA LINC01133 functions as an miRNA sponge to mediate OS tumorigenicity. In this study, we found that the expression level of LINC01133 was statistically upregulated in OS tumor tissue and cell lines compared to noncancerous tissues and a normal human osteoplastic cell line. LINC01133 silencing could also observably suppress the proliferation, migration, and invasion of OS cells (HOS and U2-OS). Bioinformatics analysis predicted that LINC01133 specifically targeted miR-422a, which was validated by dual-luciferase reporter assay. Furthermore, functional experiments revealed that miR-422a played a tumor-suppressive role in OS progression and could effectively reverse the function of LINC01133. In summary, our study discovered that lncRNA LINC01133 aggravates the proliferation, migration, and invasion of OS by sponging miR-422a, which provides a novel insight in the tumorigenesis of OS.

Key words: Osteosarcoma (OS); LINC01133; miR-422a; Long noncoding RNAs (lncRNAs); miRNA sponge

Address correspondence to Fa-Bo Feng, Department of Orthopedics, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, No. 158 Shangtang Road, Hangzhou, Zhejiang 310014, P.R. China. Tel: +86-0571-85239988; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 26, pp. 345-352, 2018
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DOI: https://doi.org/10.3727/096504017X14953948675449
E-ISSN 1555-3906
Copyright ©2018 Cognizant, LLC.
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Long Noncoding RNA ANRIL Promotes Cervical Cancer Development by Acting as a Sponge of miR-186

Jun-Jun Zhang,* Dan-Dan Wang,* Chen-Xiang Du,† and Yan Wang‡

*Department of Obstetrics and Gynecology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan Province, P.R. China
†Department of Obstetrics, People’s Hospital of Zhengzhou University, Zhengzhou, Henan Province, P.R. China
‡Department of Gynecology, The First Affiliated Hospital of Henan University of Science and Technology in The New Area, Luoyang, Henan Province, P.R. China

Cervical cancer is a common malignancy of the female reproductive system. Long noncoding RNAs (lncRNAs) have been reported to modulate tumor progression in multiple cancers. The lncRNA antisense noncoding RNA in the INK4 locus (ANRIL) has been identified as an oncogenic molecular target in several tumors; however, the function and underlying mechanism involved in cervical cancer oncogenesis are still unclear. In the present study, RT-PCR showed that ANRIL expression was significantly upregulated in cervical cancer tumors and cell lines. Nevertheless, ANRIL knockdown transfected with interference oligonucleotide inhibited the proliferation activity and invasive ability, and promoted apoptosis of cervical cancer cell lines. The bioinformatics prediction program and luciferase assay predicted and validated that miR-186 directly targeted ANRIL. The expression level of miR-186 was downregulated in cervical cancer tumors and cell lines and was negatively correlated to that of ANRIL. Moreover, rescue experiments showed that miR-186 inhibitor could reverse the suppression of ANRIL knockdown. In summary, our study demonstrated that the ANRIL/miR-186 axis might play a vital role in cervical cancer tumorigenesis.

Key words: Cervical cancer; ANRIL; miR-186; Long noncoding RNAs (lncRNAs)

Address correspondence to Yan Wang, Department of Gynecology, The First Affiliated Hospital of Henan University of Science and Technology in The New Area, Xuefu Road, New District, Luoyang, 471000 Henan 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. 26, pp. 353-361, 2018
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DOI: https://doi.org/10.3727/096504017X15002869385155
E-ISSN 1555-3906
Copyright ©2018 Cognizant, LLC.
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Long Noncoding RNA HOTAIR: An Oncogene in Human Cervical Cancer Interacting With MicroRNA-17-5p

Fei Ji,1 Delinaer Wuerkenbieke,1 Yan He, Yan Ding, and Rong Du

Department of Gynecology, The First Affiliated Hospital of Xinjiang Medical University, Urumchi, P.R. China

Increasing evidence has indicated that long noncoding RNAs (lncRNAs) are a class of significant regulators in various tumorigenesis processes. The lncRNA homeobox transcript antisense RNA (HOTAIR) has been reported to act as a functional lncRNA in cervical cancer development. The present study investigated the underlying mechanism of HOTAIR and miR-17-5p in cervical cancer tumorigenesis. The results showed that HOTAIR expression was significantly upregulated in both cervical cancer tissues and cell lines. Loss-of-function experiments showed that HOTAIR knockdown inhibited the proliferation, migration, and invasion of cervical cells. In addition, miR-17-5p expression was downregulated in cervical cancer tissues and cell lines. Pearson’s correlation analysis indicated that miR-17-5p expression was negatively correlated to that of HOTAIR. Luciferase reporter assay revealed that miR-17-5p directly targeted HOTAIR 3′-UTR. Rescue experiments showed that miR-17-5p knockdown could reverse the tumor-suppressing effect caused by si-HOTAIR transfection. In summary, our results reveal the tumor-promoting role of HOTAIR in cervical cancer via sponging miR-17-5p, providing a novel therapeutic target for future treatment of cervical cancer.

Key words: Cervical cancer; HOTAIR; Tumorigenesis; miR-7-5p

1These authors provided equal contribution to this work.
Address correspondence to Rong Du, Department of Gynecology, The First Affiliated Hospital of Xinjiang Medical University, No. 137 Liyushan South Road, Urumchi 830000, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 26, pp. 363-372, 2018
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DOI: https://doi.org/10.3727/096504017X14953948675421
E-ISSN 1555-3906
Copyright ©2018 Cognizant, LLC.
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miR-3188 Regulates Cell Proliferation, Apoptosis, and Migration in Breast Cancer by Targeting TUSC5 and Regulating the p38 MAPK Signaling Pathway

Xiaowen Chen*1 and Jianli Chen†1

*Department of Oncology Center, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong, P.R. China
†The Third Department of Medical Oncology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, P.R. China

This study intended to investigate the effects of miR-3188 on breast cancer and to reveal the possible molecular mechanisms. miR-3188 was upregulated and TUSC5 was downregulated in breast cancer tissues and MCF-7 cells compared to normal tissue and MCF-10 cells. After MCF-7 cells were transfected with miR-3188 inhibitor, cell proliferation and migration were inhibited, whereas apoptosis was promoted. Luciferase reporter assay suggested that TUSC5 was a target gene of miR-3188. In addition, miR-3188 overexpression increased the p-p38 expression, while miR-3188 suppression decreased the p-p38 expression significantly. miR-3188 regulated breast cancer progression via the p38 MAPK signaling pathway. In conclusion, miR-3188 affects breast cancer cell proliferation, apoptosis, and migration by targeting TUSC5 and activating the p38 MAPK signaling pathway. miR-3188 may serve as a potential therapeutic agent for the treatment of breast cancer.

Key words: Breast cancer; miR-3188; Cell proliferation; Cell migration; Apoptosis

1These authors are co-first authors.
Address correspondence to Jianli Chen, The Third Department of Medical Oncology, The Third Affiliated Hospital of Xinxiang Medical University, No. 679 Xiangyang Road, Hongqi District, Xinxiang, Henan 453000, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 26, pp. 373-384, 2018
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DOI: https://doi.org/10.3727/096504017X14939809845080
E-ISSN 1555-3906
Copyright ©2018 Cognizant, LLC.
Printed in the USA. All rights reserved.

Histone Demethylase JARID1B Is Overexpressed in Osteosarcoma and Upregulates Cyclin D1 Expression via Demethylation of H3K27me3

Wei Wang, Ke Zheng, Yi Pei, and XiaoJing Zhang

Department of Bone and Soft-Tissue Tumor Surgery, Cancer Hospital of China Medical University, Shenyang, Liaoning Province, P.R. China

JARID1B has been proven to be upregulated in many human malignancies and is correlated with tumor progression. However, its expression and clinical significance in osteosarcoma are still unclear. Thus, the aim of this study was to explore the effects of JARID1B in osteosarcoma tumorigenesis and development. In this study, we found that the expression levels of JARID1B in osteosarcoma tissues were significantly higher than those in corresponding noncancerous bone tissues. In addition, JARID1B upregulation occurred more frequently in osteosarcoma specimens from patients with a poor prognosis. After JARID1B transfection in osteosarcoma cells, cell proliferation was significantly promoted in vitro and in vivo. On the contrary, knockdown of JARID1B inhibited cell proliferation in vitro and tumor growth in vivo. JARID1B can also decrease the G0/G1 phase cell numbers and increase the S and G2/M phase cell numbers. We further demonstrated that JARID1B regulates cyclin D1 expression through H3K27me3. These findings indicate that JARID1B may act not only as a novel diagnostic and prognostic marker but also as a potential target for molecular therapy in osteosarcoma.

Key words: JARID1B; Osteosarcoma; Proliferation; Cyclin D1; H3K27me3

Address correspondence to XiaoJing Zhang, Department of Bone and Soft-Tissue Tumor Surgery, Cancer Hospital of China Medical University, No. 44 Xiaoheyan Road, Dadong District, Shenyang 110042, 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. 26, pp. 385-400, 2018
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DOI: https://doi.org/10.3727/096504017X14973124850905
E-ISSN 1555-3906
Copyright ©2018 Cognizant, LLC.
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MicroRNA-138 Inhibits Cell Growth, Invasion, and EMT of Non-Small Cell Lung Cancer via SOX4/p53 Feedback Loop

Dandan Li,* Changjun He,† Junfeng Wang,† Yanbo Wang,† Jianlong Bu,† Xianglong Kong,† and Dawei Sun†

*Department of Pediatrics, Cancer Hospital of the Harbin Medical University, Harbin, P.R. China
†Department of Thoracic Surgery, Cancer Hospital of the Harbin Medical University, Harbin, P.R. China

Many studies have shown that downregulation of miR-138 occurs in a variety of cancers including non-small cell lung cancer (NSCLC). However, the precise mechanisms of miR-138 in NSCLC have not been well clarified. In this study, we investigated the biological functions and molecular mechanisms of miR-138 in NSCLC cell lines, discussing whether it could turn out to be a therapeutic biomarker of NSCLC in the future. In our study, we found that miR-138 is downregulated in NSCLC tissues and cell lines. Moreover, the low level of miR-138 was associated with increased expression of SOX4 in NSCLC tissues and cell lines. Upregulation of miR-138 significantly inhibited proliferation of NSCLC cells. In addition, invasion and EMT of NSCLC cells were suppressed by overexpression of miR-138. However, downregulation of miR-138 promoted cell growth and metastasis of NSCLC cells. Bioinformatics analysis predicted that SOX4 was a potential target gene of miR-138. Next, luciferase reporter assay confirmed that miR-138 could directly target SOX4. Consistent with the effect of miR-138, downregulation of SOX4 by siRNA inhibited proliferation, invasion, and EMT of NSCLC cells. Overexpression of SOX4 in NSCLC cells partially reversed the effect of miR-138 mimic. In addition, decreased SOX4 expression could increase the level of miR-138 via upregulation of p53. Introduction of miR-138 dramatically inhibited growth, invasion, and EMT of NSCLC cells through a SOX4/p53 feedback loop.

Key words: Non-small cell lung cancer (NSCLC); MicroRNA-138 (miR-138); Sex-determining region Y (SRY)-related high-mobility group (HMG)-box 4 (SOX4); Proliferation; Invasion; Epithelial–mesenchymal transition (EMT)

Address correspondence to Dr. Dawei Sun, Department of Thoracic Surgery, Cancer Hospital of the Harbin Medical University, Baojian Road, Harbin 150081, P.R. China. Tel: +86-045-185718230; Fax: +86-045-185718230; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 26, pp. 401-410, 2018
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DOI: https://doi.org/10.3727/096504017X15017209042610
E-ISSN 1555-3906
Copyright ©2018 Cognizant, LLC.
Printed in the USA. All rights reserved.

Decreased Expression of miR-138-5p by lncRNA H19 in Cervical Cancer Promotes Tumor Proliferation

Lei Ou,* Dazhong Wang,† Han Zhang,* Qian Yu,* and Fangfang Hua‡

*Department of Gynecology and Obstetrics, Zhengzhou People’s Hospital, Zhengzhou, P.R. China
†Department of Traditional Chinese Medicine, Zhengzhou People’s Hospital, Zhengzhou, P.R. China
‡Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xinxiang Medical University, Weihui, P.R. China

MicroRNAs (miRNAs) play important roles in the carcinogenesis of cervical cancer. However, the expression and underlying mechanisms of miRNA in cervical cancer progression remain unclear. In the present study, our data showed that the expression of miR-138-5p was significantly downregulated in cervical cancer tissues, and decreased expression of miR-138-5p was correlated with advanced FIGO stage, poor differentiation, lymph node metastasis, and poor overall survival of cervical cancer patients. Function assays showed that overexpression of miR-138-5p reduced cervical cancer cell proliferation, arrested cells in the G0/G1 phase, and induced cell apoptosis in vitro. Remarkably, SIRT1 was confirmed as a direct target of miR-138-5p in cervical cancer, and miR-138-5p exerted the reduced tumor functions by suppressing SIRT1 expression. Moreover, we further identified that lncRNA H19 could act as a molecular sponge of miR-138-5p in cervical cancer progression. Taken together, these results suggested that miR-138-5p could suppress cervical cancer cell progression by targeting SIRT1.

Key words: miR-138-5p; Long noncoding RNA (lncRNA) H19; SIRT1; Cervical cancer

Address correspondence to Lei Ou, Department of Gynecology and Obstetrics, Zhengzhou People’s Hospital, No. 33 Huanghe Road, Zheng Zhou, 450003 Henan, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 26, pp. 411-420, 2018
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DOI: https://doi.org/10.3727/096504017X14974343584989
E-ISSN 1555-3906
Copyright ©2018 Cognizant, LLC.
Printed in the USA. All rights reserved.

MicroRNA-139-5p Inhibits Cell Proliferation and Invasion by Targeting RHO-Associated Coiled-Coil-Containing Protein Kinase 2 in Ovarian Cancer

Yanli Wang,* Jia Li,† Chunling Xu,† and Xiaomeng Zhang†

*Department of Gynecology, The First Hospital of Jilin University, Changchun, P.R. China
†Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, P.R. China

Increasing evidence indicates that the dysregulation of microRNAs is associated with the development and progression of various cancers. MicroRNA-139-5p (miR-139-5p) has been reported to have a tumor suppressive role in many types of cancers. The role of miR-139-5p in ovarian cancer (OC) is poorly understood. The purpose of the present study was to explore the expression of miR-139-5p and its function in OC. The results showed that miR-139-5p expression was markedly downregulated in OC tissues and cell lines. In addition, underexpression of miR-139-5p was significantly associated with FIGO stage, lymph mode metastasis, and poor overall survival of OC patients. Functional analyses indicated that overexpression of miR-139-5p significantly inhibited proliferation, colony formation, migration, and invasion of OC cells. Rho-associated coiled-coil-containing protein kinase 2 (ROCK2) was identified as a direct target of miR-139-5p using luciferase reporter assays, qualitative real-time reverse transcriptase PCR (qRT-PCR), and Western blot. In addition, ROCK2 expression was upregulated and was inversely correlated with miR-139-5p levels in OC tissues. Rescue experiments showed that overexpression of ROCK2 effectively reversed the inhibitory effect of OC cells induced by miR-139-5p. Most interestingly, in vivo studies indicated that miR-139-5p markedly suppressed the growth of tumors by repressing ROCK2 expression in nude mice. Taken together, these findings demonstrated that miR- 139-5p plays an important tumor suppressor role in OC by directly binding to ROCK2, providing a novel target for the molecular treatment of OC.

Key words: MicroRNAs; miR-139-5p; Ovarian cancer (OC); ROCK2; Proliferation; Invasion

Address correspondence to Xiaomeng Zhang, Department of Ophthalmology, The Second Hospital of Jilin University, 218# Ziqiang Street, Nanguan District, Changchun 130041, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 26, pp. 421-429, 2018
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DOI: https://doi.org/10.3727/096504017X15049221237147
E-ISSN 1555-3906
Copyright ©2018 Cognizant, LLC.
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ClC5 Decreases the Sensitivity of Multiple Myeloma Cells to Bortezomib via Promoting Prosurvival Autophagy

Huimin Zhang,*† Yuhui Pang,† Chuanbao Ma,† Jianying Li,† Huaquan Wang,* and Zonghong Shao*

*Department of Hematopathology, Tianjin Medical University General Hospital, Tianjin, P.R. China
†Department of Hematology, Shijiazhuang Ping’an Hospital, Shijiazhuang, Hebei, P.R. China

Resistance to bortezomib (BZ) is the major problem that largely limits its clinical application in multiple myeloma treatment. In the current study, we investigated whether ClC5, a member of the chloride channel family, is involved in this process. The MTT assay showed that BZ treatment decreased cell viability in three multiple myeloma cell lines (ARH77, U266, and SKO-007), with IC50 values of 2.83, 4.37, and 1.91 nM, respectively. Moreover, BZ increased the conversion of LC3B-I to LC3B-II and expressions of beclin-1 and ATG5, concomitantly with a decreased p62 expression. Pharmacological inhibition of autophagy with 3-MA facilitated cell death in response to BZ treatment. Additionally, BZ increased ClC5 protein expression in ARH77, U266, and SKO-007 cells. Knockdown of ClC5 with small interfering RNA sensitized cells to BZ treatment, and upregulation of ClC5 induced chemoresistance to BZ. Furthermore, ClC5 downregulation promoted BZ-induced LC3B-I to LC3B-II conversion and beclin-1 expression, whereas overexpression of ClC5 showed the opposite results in ARH77 cells. Finally, BZ induced dephosphorylation of AKT and mTOR, which was significantly attenuated by ClC5 inhibition. However, ClC5 upregulation further enhanced AKT and mTOR dephosphorylation induced by BZ. Our study demonstrates that ClC5 induces chemoresistance of multiple myeloma cells to BZ via increasing prosurvivalautophagy by inhibiting the AKT–mTOR pathway. These data suggest that ClC5 may play a critical role in future multiple myeloma treatment strategies.

Key words: Bortezomib (BZ); Multiple myeloma; Chemoresistance; Autophagy; ClC5; AKT–mTOR pathway

Address correspondence to Zonghong Shao, Department of Hematopathology, Tianjin Medical University General Hospital, No. 154 Anshan Road, Heping District, Tianjin 300052, P.R. China. Tel: 86-022-60817092; Fax: 86-022-60817092; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 26, pp. 431-444, 2018
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X15031557924123
E-ISSN 1555-3906
Copyright ©2018 Cognizant, LLC.
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β-1,3-Galactosyl-O-Glycosyl-Glycoprotein β-1,6-N-Acetylglucosaminyltransferase 3 Increases MCAM Stability, Which Enhances S100A8/A9-Mediated Cancer Motility

I Wayan Sumardika,*† Chen Youyi,* Eisaku Kondo,‡ Yusuke Inoue,§ I Made Winarsa Ruma,*† Hitoshi Murata,* Rie Kinoshita,* Ken-Ichi Yamamoto,* Shuta Tomida,¶ Kazuhiko Shien,# Hiroki Sato,# Akira Yamauchi,** Junichiro Futami,†† Endy Widya Putranto,‡‡ Toshihiko Hibino,§§ Shinichi Toyooka,¶#¶¶ Masahiro Nishibori,## and Masakiyo Sakaguchi*

*Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
†Faculty of Medicine, Udayana University, Bali, Indonesia
‡Division of Molecular and Cellular Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
§Faculty of Science and Technology, Division of Molecular Science, Gunma University, Gunma, Japan
¶Department of Biobank, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
#Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
**Department of Biochemistry, Kawasaki Medical School, Okayama, Japan
††Department of Medical and Bioengineering Science, Okayama University Graduate School of Natural Science and Technology, Okayama, Japan
‡‡Department of Pediatrics, Dr. Sardjito Hospital/Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
§§Department of Dermatology, Tokyo Medical University, Tokyo, Japan
¶¶Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
##Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

We previously identified novel S100A8/A9 receptors, extracellular matrix metalloproteinase inducer (EMMPRIN), melanoma cell adhesion molecule (MCAM), activated leukocyte cell adhesion molecule (ALCAM), and neuroplastin (NPTN) β, that are critically involved in S100A8/A9-mediated cancer metastasis and inflammation when expressed at high levels. However, little is known about the presence of any cancer-specific mechanism(s) that modifies these receptors, further inducing upregulation at protein levels without any transcriptional regulation. Expression levels of glycosyltransferase-encoding genes were examined by a PCR-based profiling array followed by confirmation with quantitative real-time PCR. Cell migration and invasion were assessed using a Boyden chamber. Western blotting was used to examine the protein level, and the RNA level was examined by Northern blotting. Immunohistochemistry was used to examine the expression pattern of β-1,3-galactosyl-O-glycosyl-glycoprotein β-1,6-N-acetylglucosaminyltransferase 3 (GCNT3) and MCAM in melanoma tissue. We found that GCNT3 is overexpressed in highly metastatic melanomas. Silencing and functional inhibition of GCNT3 greatly suppressed migration and invasion of melanoma cells, resulting in the loss of S100A8/A9 responsiveness. Among the novel S100A8/A9 receptors, GCNT3 favorably glycosylates the MCAM receptor, extending its half-life and leading to further elevation of S100A8/A9-mediated cellular motility in melanoma cells. GCNT3 expression is positively correlated to MCAM expression in patients with high-grade melanomas. Collectively, our results showed that GCNT3 is an upstream regulator of MCAM protein and indicate the possibility of a potential molecular target in melanoma therapeutics through abrogation of the S100A8/A9–MCAM axis.

Key words: S100A8/A9; GCNT3; Glycosylation; Receptor; Metastasis

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. 26, pp. 445-455, 2018
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DOI: https://doi.org/10.3727/096504017X14974834436195
E-ISSN 1555-3906
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miR-205 Inhibits Neuroblastoma Growth by Targeting cAMP-Responsive Element-Binding Protein 1

Shu Chen,* Lianhua Jin,† Shu Nie,† Lizhi Han,† Na Lu,† and Yan Zhou†

*Department of Thoracic Surgery, The Second Hospital of Jilin University, Changchun, P.R. China
†Department of Pediatrics, The First Hospital of Jilin University, Changchun, P.R. China

Accumulating evidence indicates that microRNA-205 (miR-205) is involved in tumor initiation, development, and metastasis in various cancers. However, its functions in neuroblastoma (NB) remain largely unclear. Here we found that miR-205 was significantly downregulated in human NB tissue samples and cell lines. miR-205 expression was lower in poorly differentiated NB tissues and those of advanced International Neuroblastoma Staging System stage. In addition, restoration of miR-205 in NB cells suppressed proliferation, migration, and invasion and induced cell apoptosis in vitro, as well as impaired tumor growth in vivo. cAMP-responsive element-binding protein 1 (CREB1) was identified as a direct target gene of miR-205. Expression of an miR-205 mimic in NB cells significantly diminished expression of CREB1 and the CREB1 targets BCL-2 and MMP9. CREB1 was also found to be upregulated in human NB tissues, its expression being inversely correlated with miR-205 expression (r = −0.554, p = 0.003). Importantly, CREB1 upregulation partially rescued the inhibitory effects of miR-205 on NB cells. These findings suggest that miR-205 may function as a tumor suppressor in NB by targeting CREB1.

Key words: Neuroblastoma (NB); miR-205; CREB1; Proliferation; Invasion

Address correspondence to Yan Zhou, Department of Pediatrics, The First Hospital of Jilin University, #71 Xinmin Street, Chaoyang District, Changchun 130021, P.R. China. Tel: +860431-88782222; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 26, pp. 457-466, 2018
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DOI: https://doi.org/10.3727/096504017X15035025554553
E-ISSN 1555-3906
Copyright ©2018 Cognizant, LLC.
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MicroRNA-384 Inhibits the Growth and Invasion of Renal Cell Carcinoma Cells by Targeting Astrocyte Elevated Gene 1

Haitao Song,* Yanwei Rao,† Gang Zhang,* and Xiangbo Kong*

*Department of Urinary Surgery, China–Japan Union Hospital, Jilin University, Changchun, P.R. China
†Department of Critical Care Medicine, Jilin Province People’s Hospital, Changchun, P.R. China

MicroRNAs (miRNAs) are emerging as pivotal regulators in the development and progression of various cancers, including renal cell carcinoma (RCC). MicroRNA-384 (miR-384) has been found to be an important cancer-related miRNA in several types of cancers. However, the role of miR-384 in RCC remains unclear. In this study, we aimed to investigate the potential function of miR-384 in regulating tumorigenesis in RCC. Here we found that miR-384 was significantly downregulated in RCC tissues and cell lines. Overexpression of miR-384 significantly inhibited the growth and invasion of RCC cells, whereas inhibition of miR-384 had the opposite effects. Bioinformatic analysis and luciferase reporter assay showed that miR-384 directly targeted the 3′-untranslated region of astrocyte elevated gene 1 (AEG-1). Further data showed that miR-384 could negatively regulate the expression of AEG-1 in RCC cells. Importantly, miR-384 expression was inversely correlated with AEG-1 expression in clinical RCC specimens. Moreover, miR-384 regulates the activation of Wnt signaling. Overexpression of AEG-1 significantly reversed the antitumor effects of miR-384. Overall, these findings suggest that miR-384 suppresses the growth and invasion of RCC cells via downregulation of AEG-1, providing a potential therapeutic target for the treatment of RCC.

Key words: Astrocyte elevated gene 1 (AEG-1); miR-384; Renal cell carcinoma (RCC)

Address correspondence to Xiangbo Kong, Department of Urinary Surgery, China–Japan Union Hospital, Jilin University, 126 Xiantai Street,

Changchun, Jilin 130033, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 26, pp. 467-472, 2018
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X15040166233313
E-ISSN 1555-3906
Copyright ©2018 Cognizant, LLC.
Printed in the USA. All rights reserved.

Photo-Activatable Akt Probe: A New Tool to Study the Akt-Dependent Physiopathology of Cancer Cells

Sanae Haga,* Takeaki Ozawa,† Naoki Morita,‡ Mami Asano,§ Shigeki Jin,¶ Yimin,# and Michitaka Ozaki*§¶

*Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan
†Department of Chemistry, School of Science, The University of Tokyo, Tokyo, Japan
‡Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Sapporo, Hokkaido, Japan
§Laboratory of Molecular and Functional Bioimaging, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan
¶Core Research Laboratory, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan
#Department of Advanced Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan

Akt is commonly overexpressed and activated in cancer cells and plays a pivotal role in cell survival, protection, and chemoresistance. Therefore, Akt is one of the target molecules in understanding characters of cancer cells and developing anticancer drugs. Here we examined whether a newly developed photo-activatable Akt (PA-Akt) probe, based on a light-inducible protein interaction module of plant cryptochrome2 (CRY2) and cryptochrome-interacting basic helix–loop–helix (CIB1), can regulate Akt-associated cell functions. By illuminating blue light to the cells stably transfected with PA-Akt probe, CRY2-Akt (a fusion protein of CRY2 and Akt) underwent a structural change and interacted with Myr-CIBN (myristoylated N-terminal portion of CIB1), anchoring it at the cell membrane. Western blot analysis revealed that S473 and T308 of the Akt of probe-Akt were sequentially phosphorylated by intermittent and continuous light illumination. Endogenous Akt and GSK-3β, one of the main downstream signals of Akt, were also phosphorylated, depending on light intensity. These facts indicate that photo-activation of probe-Akt can activate endogenous Akt and its downstream signals. The photo-activated Akt conferred protection against nutritional deprivation and H2O2 stresses to the cells significantly. Using the newly developed PA-Akt probe, endogenous Akt was activated easily, transiently, and repeatedly. This probe will be a unique tool in studying Akt-associated specific cellular functions in cancer cells and developing anticancer drugs.

Key words: Photo-activatable probe; Akt; Nutritional deprivation; Oxidative stress

Address correspondence to Michitaka Ozaki, M.D., Ph.D., Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido University, N12W5, Kita-Ku, Sapporo, Hokkaido 060-0812, Japan. Tel: +81-11-706-3337; Fax: +81-11-706-3337; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 26, pp. 473-481, 2018
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X15105708598531
E-ISSN 1555-3906
Copyright ©2018 Cognizant, LLC.
Printed in the USA. All rights reserved.

The Long Noncoding RNA HOTAIR Promotes Colorectal Cancer Progression by Sponging miR-197

Xinyang Lu, Zhiqiang Liu, Xiaofei Ning, Lunhua Huang, and Biao Jiang

Department of Gastrointestinal Surgery, Affiliated Hospital of Jining Medical University, Jining, P.R. China

The long noncoding RNA HOX transcript antisense RNA (HOTAIR) has been found to be overexpressed in many human malignancies and involved in tumor progression and metastasis. Although the downstream target through which HOTAIR modulates tumor metastasis is not well known, evidence suggests that microRNA-197 (miR-197) might be involved in this event. In the present study, the significance of HOTAIR and miR-197 in the progression of colorectal cancer was detected in vitro and in vivo. We found that HOTAIR expression was significantly increased in colorectal cancer cells and tissues. In contrast, the expression of miR-197 was obviously decreased. We further demonstrated that HOTAIR knockdown promoted apoptosis and inhibited cell proliferation, migration, and invasion in vitro and in vivo. Moreover, HOTAIR modulated the progression of colorectal cancer by competitively binding miR-197. Taken together, our study has identified a novel pathway through which HOTAIR exerts its oncogenic role and provided a molecular basis for potential applications of HOTAIR in the prognosis and treatment of colorectal cancer.

Key words: Colorectal cancer; Long noncoding RNAs (lncRNAs); HOTAIR; miR-197

Address correspondence to Biao Jiang, Department of Gastrointestinal Surgery, Affiliated Hospital of Jining Medical University, No. 89 Guhuai Road, Rencheng District, Jining, Shandong 272000, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 26, pp. 483-494, 2018
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X14941825760362
E-ISSN 1555-3906
Copyright ©2018 Cognizant, LLC.
Printed in the USA. All rights reserved.

Tanshinone Suppresses Arecoline-Induced Epithelial–Mesenchymal Transition in Oral Submucous Fibrosis by Epigenetically Reactivating the p53 Pathway

Lian Zheng, Zhen-Jie Guan, Wen-Ting Pan, Tian-Feng Du, and Yu-Jia Zhai, Jia Guo

Oral and Maxillofacial Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China

Oral submucous fibrosis (OSF) induced by chewing of the areca nut has been considered to be a precancerous lesion with a high probability of developing oral squamous cell carcinoma. Tanshinone (TSN) is the main component extracted from Salvia miltiorrhiza, a traditional Chinese medicine, which was found to have diverse pharmacological effects, such as anti-inflammatory and antitumor. In the current study, we aimed to identify the inhibitory effects and the underlying mechanism of TSN on OSF progress. We found that treatment with TSN inhibited the arecoline-mediated proliferation of primary human oral mucosal fibroblasts and reversed the promotive effects of arecoline on the EMT process. By RNA deep sequencing, we screened two possible targets for TSN: LSD1 and p53. We confirmed that p53 is much lower in OSF than in normal mucous tissues. In addition, p53 and its downstream molecules were decreased by arecoline treatment in oral mucosal fibroblasts, which was reversed by treatment with TSN in a dose-dependent manner. Our results also revealed that arecoline stimulation resulted in hypermethylation of the promoter of TP53 and subsequent downregulation of p53 levels, which was reversed by TSN. Furthermore, we identified that LSD1 could epigenetically activate TP53 by recruiting H3K27me1 and H3K4m2 to its promoter. Our findings provide new insights into the mechanism by which TSN influences arecoline-induced OSF and rationale for the development of clinical intervention strategies for OSF and even oral squamous cell carcinoma.

Key words: Oral submucous fibrosis (OSF); Areca nut; Oral squamous cell carcinoma; Tanshinone (TSN); Epithelial–mesenchymal transition (EMT); p53; Methylation

Address correspondence to Professor Jia Guo, Department of Endodontics, The First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 26, pp. 495-502, 2018
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X14982578608217
E-ISSN 1555-3906
Copyright ©2018 Cognizant, LLC.
Printed in the USA. All rights reserved.

Dexmedetomidine Inhibits Osteosarcoma Cell Proliferation and Migration, and Promotes Apoptosis by Regulating miR-520a-3p

Xiaoyan Wang,* Yongguang Xu,* Xinlei Chen,* and Jianmin Xiao†

*Department of Anesthesiology, Shandong Provincial Hospital Affiliated With Shandong University, Jinan, Shandong, P.R. China
†Department of Anesthesiology, Ningjin People’s Hospital, Ningjin, Shandong, P.R. China

This study aimed to investigate the effect of dexmedetomidine (DEX) on osteosarcoma (OS) cell line MG63 and to explore the possible relationship between DEX and miR-520-3p in OS. The results showed that DEX could upregulate miR-520-3p, which directly targeted AKT1. Additionally, miR-520-3p also inhibited MG63 cell proliferation and migration, promoted apoptosis, and suppressed protein expressions of AKT, p-AKT, p-mTOR, and p-ERK1/2. DEX can inhibit OS cell proliferation and migration and promote apoptosis by upregulating the expression level of miR-520a-3p. DEX may serve as a potential therapeutic agent in OS treatment, and miR-520a-3p may be a potential target in the therapy of OS.

Key words: Osteosarcoma (OS); Dexmedetomidine (DEX); miR-520a-3p; Cell proliferation and migration; AKT and ERK pathways

Address correspondence to Jianmin Xiao, Department of Anesthesiology, Ningjin People’s Hospital, No. 37 Kangping Street, Ningjin, Shandong 253400, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it



Oncology Research, Vol. 26, pp. 503-513, 2018
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X15005102445191
E-ISSN 1555-3906
Copyright ©2018 Cognizant, LLC.
Printed in the USA. All rights reserved.

Detection of Necroptosis in Ligand-Mediated and Hypoxia-Induced Injury of Hepatocytes Using a Novel Optic Probe-Detecting Receptor-Interacting Protein (RIP)1/RIP3 Binding

Sanae Haga,* Akira Kanno,† Takeaki Ozawa,‡ Naoki Morita,§ Mami Asano,¶ and Michitaka Ozaki*¶

*Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan
†Department of Environmental Applied Chemistry, Faculty of Engineering, University of Toyama, Toyama, Japan
‡Department of Chemistry, School of Science, The University of Tokyo, Tokyo, Japan
§Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Sapporo, Hokkaido, Japan
¶Laboratory of Molecular and Functional Bio-Imaging, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan

Liver injury is often observed in various pathological conditions including posthepatectomy state and cancer chemotherapy. It occurs mainly as a consequence of the combined necrotic and apoptotic types of cell death. In order to study liver/hepatocyte injury by the necrotic type of cell death, we studied signal-regulated necrosis (necroptosis) by developing a new optic probe for detecting receptor-interacting protein kinase 1 (RIP)/RIP3 binding, an essential process for necroptosis induction. In the mouse hepatocyte cell line, TIB-73 cells, TNF-α/cycloheximide (T/C) induced RIP1/3 binding only when caspase activity was suppressed by the caspase-specific inhibitor z-VAD-fmk (zVAD). T/C/zVAD-induced RIP1/3 binding was inhibited by necrostatin-1 (Nec-1), an allosteric inhibitor of RIP1. The reduced cell survival by T/C/zVAD was improved by Nec-1. These facts indicate that T/C induces necroptosis of hepatocytes when the apoptotic pathway is inhibited/unavailable. FasL also induced cell death, which was only partially inhibited by zVAD, indicating the possible involvement of necroptosis rather than apoptosis. FasL activated caspase 3 and, similarly, induced RIP1/3 binding when the caspases were inactivated. Interestingly, FasL-induced RIP1/3 binding was significantly suppressed by the antioxidants Trolox and N-acetyl cysteine (NAC), suggesting the involvement of reactive oxygen species (ROS) in FasL-induced necroptotic cellular processes. H2O2, by itself, induced RIP1/3 binding that was suppressed by Nec-1, but not by zVAD. Hypoxia induced RIP1/3 binding after reoxygenation, which was suppressed by Nec-1 or by the antioxidants. Cell death induced by hypoxia/reoxygenation (H/R) was also improved by Nec-1. Similar to H2O2, H/R did not require caspase inhibition for RIP1/3 binding, suggesting the involvement of a caspase-independent mechanism for non-ligand-induced and/or redox-mediated necroptosis. These data indicate that ROS can induce necroptosis and mediate the FasL- and hypoxia-induced necroptosis via a molecular mechanism that differs from a conventional caspase-dependent pathway. In conclusion, necroptosis is potentially involved in liver/hepatocyte injury induced by oxidative stress and FasL in the absence of apoptosis.

Key words: Regulated cell death; Necroptosis; Reactive oxygen species (ROS); Fas ligand; Hypoxia/reoxygenation

Address correspondence to Michitaka Ozaki, M.D., Ph.D., Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido University, N12, W5, Kita-ku, Sapporo, Hokkaido 060-0812, Japan. Tel: +81-11-706-3337; Fax: +81-11-706-3337; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 26, pp. 515-518, 2018
0965-0407/17 $90.00 +.00
DOI: https://doi.org/10.3727/096504017X15128550060375
E-ISSN 1555-3906
Copyright ©2018 Cognizant, LLC.
Printed in the USA. All rights reserved.

Normalization of Elevated Tumor Marker CA27-29 After Bilateral Lung Transplantation in a Patient With Breast Cancer and Idiopathic Pulmonary Fibrosis

Mehmet Sitki Copur,*† Julie Marie Wurdeman,† Debra Nelson,* Ryan Ramaekers,* Dron Gauchan,* and David Crockett*

*CHI St. Francis Cancer Treatment Center, Grand Island, NE, USA
†University of Nebraska Medical Center, Omaha, NE, USA

Solid tumors involving glandular organs express mucin glycoprotein that is eventually shed into the circulation. As a result, these proteins can easily be measured in the serum and be used as potential tumor markers. The most commonly used tumor markers for breast cancer are CA27-29 and CA15-3, which both measure the glycoprotein product of the mucin-1 (MUC1) gene. CA27-29 has been approved by the US Food and Drug Administration for monitoring disease activity in breast cancer patients. Most oncology clinical practice guidelines do not recommend the use of tumor markers for routine surveillance of early stage disease but recognize their utility in the metastatic setting. We present a patient with stage IIIA breast cancer and preexisting hypersensitivity pneumonitis who was found to have an elevated serum tumor marker CA27-29. After successful curative intent treatment of her early stage breast cancer, she developed gradual and progressive worsening of her lung disease with eventual development of severe pulmonary fibrosis requiring bilateral lung transplantation. As part of the pretransplant evaluation, she was found to have an elevation of serum tumor marker CA27-29. While the diagnostic evaluation, including imaging studies, was negative for the presence of recurrent disease, the serial serum tumor marker CA27-29 levels remained persistently elevated. The decision was made for her to undergo bilateral lung transplantation. Shortly after surgery, her CA27-29 tumor marker level returned to normal range, and it has continued to remain in the normal range with no evidence of breast cancer recurrence.

Key words: CA27-29; Tumor markers; Breast cancer; Pulmonary fibrosis

Address correspondence to Mehmet Sitki Copur, M.D., FACP, Medical Director of Oncology, St. Francis Cancer Treatment Center, 2116 W. Faidley Avenue, Grand Island, NE 68803, USA. Tel: 308-398-5450; Fax: 308-398-5351; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it