Oncology Research : Featuring Preclinical and Clinical Cancer Therapeutics

Co-Editors-in-Chief

American Continent:
Edward Chu
University of Pittsburgh Cancer Institute, USA
Email:  chueyale@yahoo.com

Asia and Pacific Rim:
Kazuo Umezawa
Aichi Medical University School of Medicine, Japan
Email:  umezawa@aichi-med-u.ac.jp

European Continent:
Enrico Mini
University of Florence, Italy
Email:  enrico.mini@unifi.it

Associate Editor: Lois Malehorn

EDITORIAL ADVISORY BOARD

Alan C. Sartorelli,† Founding Editor

American Continent: Edward Chu, Co-Editor-in-Chief
L. J. Appleman, University of Pittsburgh, USA
N. Bahary, University of Pittsburgh, USA
J. R. Bertino, Rutgers Cancer Institute of New Jersey, USA
J. H. Beumer, Hillman Cancer Center, USA
M. Boyiadzis, University of Pittsburgh, USA
Y.-C. Cheng, Yale University School of Medicine, USA
M. S. Copur, University of Nebraska, USA
A. Krishnamurthy, University of Pittsburgh, ISA
J. J. Lee, University of Pittsburgh, USA
Y. Li, Sanford Burnham Prebys Medical Discovery Institute, USA
G. D. Roodman, Indiana University, USA
M. Rudek, Johns Hopkins University, USA
J. C. Schmitz, University of Pittsburgh, USA
L. Zhang, University of Pittsburgh, USA

European Continent: Enrico Mini, Co-Editor-in-Chief
A. H. Calvert, University of Newcastle upon Tyne, UK
A. Di Paolo, University of Pisa, Italy
P. Workman, CRC Center for Cancer Therapeutics, UK

Asia and Pacific Rim: Kazuo Umezawa, Co-Editor-in-Chief
A. Deguchi, Tokyo Women’s Medical University, Japan
S. Gantsev, Bashkirian State Medical University, Russia
R. Horie, Kitasato University, Japan
Y. Horiguchi, Tokyo Medical University, Japan
M. Imoto, Keio University, Japan
H. Kakeya, Kyoto University, Japan
M. Kawatani, RIKEN, Japan
E. Kikuchi, Keio University, Japan
N. Koide, Aichi Medical University, Japan
Y. Lin, Aichi Medical University, Japan
J. Neuzil, Griffith University, Gold Coast Campus, Australia
O. Ohno, Keio University, Japan
T. Ohsugi, Rakuno Gakuen University, Japan
H. Osada, RIKEN, Japan
M. Oya, Keio University, Japan
M. Ozaki, Hokkaido University, Japan
Y. Sasazawa, Keio University, Japan
K. Sidthipong, Mahidol University, Thailand
S. Simizu, Keio University, Japan
M. Takeiri, Kyoto University, Japan
E. Tashiro, Keio University, Japan
T. Ueno, Kyoto University Hospital, Japan
M. Yamamoto, Waseda University, Japan

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Book:
1. Weinberg RA. The biology of cancer, 2nd ed. New York (NY): Garland Science; 2014.
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1. Hasskarl J. Sorafenib: Targeting multiple tyrosine kinases in cancer. In: Martens UM, editor. Small molecules in oncology, 2nd ed. Berlin, Germany: Springer-Verlag; 2014. p. 145-164.
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Access Current Articles (Volume 27, Number 9)

Table of Contents:

Volume 27, Number 9

Exosomal miR-1228 From Cancer-Associated Fibroblasts Promotes Cell Migration and Invasion of Osteosarcoma by Directly Targeting SCAI – 979
DOI: https://doi.org/10.3727/096504018X15336368805108

Jian-Wei Wang, Xiao-Feng Wu, Xiao-Juan Gu, and Xing-Hua Jiang

Department of Orthopedic, Kunshan Hospital of Traditional Chinese Medicine, Kunshan, Jiangsu, P.R. China

Cancer-associated fibroblasts (CAFs) play a predominant role in regulating tumor progression. Understanding how CAFs communicate with osteosarcoma is crucial for developing novel approaches for osteosarcoma therapy. Exosomes are able to transmit messages between cells. In this study, we demonstrated that CAFs transfer exosomes to osteosarcoma cells, which promotes osteosarcoma cell migration and invasion. Using a miRNA microarray analysis, we identified 13 miRNAs that are significantly increased in exosomes derived from cancer-associated fibroblasts (CAFs) and corresponding paracancer fibroblasts (PAFs). In vitro studies further validated that the levels of microRNA-1228 (miR-1228) were increased in CAFs, its secreted exosomes, and in recipient osteosarcoma cells, which can downregulate endogenous SCAI mRNA and protein level in osteosarcoma. Furthermore, our findings demonstrate that SCAI was downregulated in osteosarcoma tissues. Taken together, this study provides evidence that CAF exosomal miR-1228 is able to promote osteosarcoma invasion and migration by targeting SCAI, which may represent a critical therapeutic target for osteosarcoma treatment.

Key words: Osteosarcoma; Exosome; miRNAs; miR-1228; Cancer-associated fibroblasts (CAFs); Suppressor of cancer cell invasion (SCAI)

Nutlin-3-Induced Sensitization of Non-Small Cell Lung Cancer Stem Cells to Axitinib-Induced Apoptosis Through Repression of Akt1/Wnt Signaling – 987
DOI: https://doi.org/10.3727/096504018X15424918479652

Meng Wang,*1 Xin Wang,†1 Yuan Li,‡1 Qiang Xiao,§ Xiao-Hai Cui,* Guo-Dong Xiao,* Ji-Chang Wang,¶ Chong-Wen Xu,# Hong Ren,* and Dapeng Liu*

*Department of Thoracic Surgery and Oncology, the Second Department of Thoracic Surgery, Cancer Center, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, P.R. China
†Department of Gastroenterology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, P.R. China
‡School of Humanities and Social Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi Province, P.R. China
§Department of Medical Oncology, Cancer Center, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, P.R. China
¶Department of Vascular and Endovascular Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, P.R. China
#Department of Otorhinolaryngology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, P.R. China

The aim of this study was to investigate the potential biological activities of nutlin-3 in the regulation of growth and proliferation of non-small cell lung cancer (NSCLC) stem cells (CSCs), which may help in sensitizing to axitinib-induced apoptosis. Nutlin-3 induction of p53 expression was used to test its role in controlling the cell division pattern and apoptosis of NSCLC cells. A549 cells and H460 cells were pretreated with nutlin-3 and then treated with either an Akt1 activator or shRNA-GSK3β, to investigate the potential role of p53 sensitization in the biological effects of axitinib. We also determined the expression levels of GSK3β and p-Akt1 in patients with NSCLC and determined their potential association with survival data using Kaplan–Meier plots and CBIOTAL. Increased p53 expression stimulated the induction of apoptosis by axitinib and promoted asymmetric cell division (ACD) of NSCLC CSCs. The repression of Akt phosphorylation induced by nutlin-3 promoted the ACD of lung CSCs, decreasing the proportion of the stem cell population. In addition to the induction of apoptosis by axitinib through inhibition of Wnt signaling, nutlin-3 treatment further enhanced axitinib-induced apoptosis by inhibiting Akt1/GSK3β/Wnt signaling. The low expression of GSK3b and increased expression of p-Akt in patients with NSCLC were closely associated with the development of NSCLC. TP53 stimulates the induction of apoptosis in NSCLC by axitinib and the ACD of lung CSCs through its regulatory effects on the p53/Akt/GSK3β pathways.

Key words: Non-small cell lung cancer (NSCLC); Nutlin-3; Axitinib; Cancer stem cells (CSCs); Wnt signaling; Apoptosis; Akt; Asymmetric cell division (ACD)

miR-101 Represses T-Cell Acute Lymphoblastic Leukemia by Targeting CXCR7/STAT3 Axis – 997
DOI: https://doi.org/10.3727/096504018X15439207752093

Xue-Yi Yang and Ye Sheng

Life Science College, Luoyang Normal University, Luoyang, Henan, P.R. China

Although miR-101 is involved in the development and progression of T-cell acute lymphoblastic leukemia (T-ALL), the underlying molecular mechanisms remain unclear. In this article, we report that miR-101 expression was inversely correlated with CX chemokine receptor 7 (CXCR7) level in T-ALL. Introducing miR-101 inhibited T-ALL cell proliferation and invasion in vitro and suppressed tumor growth and lung metastasis in vivo. CXCR7 was identified as a direct target of miR-101. The inhibitory effects of miR-101 were mimicked and counteracted by CXCR7 depletion and overexpression, respectively. Mechanistically, miR-101 targets CXCR7/STAT3 axis to reduce T-ALL growth and metastasis. Overall, these findings implied the potential application of miR-101 and CXCR7 in T-ALL treatment.

Key words: MicroRNA-101 (miR-101); CXCR7; T-cell acute lymphoblastic leukemia (T-ALL)

ZBTB7/miR-137 Autoregulatory Circuit Promotes the Progression of Renal Carcinoma – 1107
DOI: https://doi.org/10.3727/096504018X15231148037228

Lihui Wang, Qi Li, Zhuo Ye, and Baoping Qiao

Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China

Renal carcinoma greatly threatens human health, but the involved molecular mechanisms are far from complete understanding. As a master oncogene driving the initiation of many other cancers, ZBTB7 has not been established to be associated with renal cancer. Our data revealed that ZBTB7 is highly expressed in renal carcinoma specimens and cell lines, compared with normal cells. The silencing of ZBTB7 suppressed the proliferation and invasion of renal cancer cells. ZBTB7 overexpression rendered normal cells with higher proliferation rates and invasiveness. An animal study further confirmed the role of ZBTB7 in the growth of renal carcinoma. Moreover, miR-137 was identified to negatively regulate the expression of ZBTB7, and its abundance is inversely correlated with that of ZBTB7 in renal carcinoma specimens and cell lines. ZBTB7 overexpression may be induced by miR-137 downregulation. Interestingly, ZBTB7 can also suppress miR-137 expression by binding to its recognition site within the miR-137 promoter region. Taken together, we identified an autoregulatory loop consisting of ZBTB7 and miR-137 in gastric cancers, and targeting this pathway may be an effective strategy for renal carcinoma cancer therapy.

Key words: miR-137; ZBTB7; Renal carcinoma

miR-185 Inhibits the Proliferation and Invasion of Non-Small Cell Lung Cancer by Targeting KLF7 – 1015
DOI: https://doi.org/10.3727/096504018X15247341491655

Lili Zhao,* Yao Zhang,* Jiaoxia Liu,* Wei Yin,† Dan Jin,‡ Dandan Wang,* and Wei Zhang*

*Affiliated Hongqi Hospital of Mudanjiang Medical University, Mudanjiang City, P.R. China
†Mudanjiang Forestry Hospital, Mudanjiang City, P.R. China
‡Mudanjiang Women and Children’s hospital, Mudanjiang City, P.R. China

MicroRNAs (miRNAs) are short endogenous noncoding RNAs that frequently play vital roles in many cancer types. Herein we demonstrated that miR-185 was remarkably downregulated in NSCLC tissues compared with adjacent normal tissues. A lower level of miR-185 was associated with lymph node metastasis. Functional assays showed that upregulation of miR-185 inhibited the proliferation, colony formation, and invasion capacities of NSCLC cells in vitro. Furthermore, we found that miR-185 suppressed the epithelial–mesenchymal transition (EMT) process. Bioinformatics analysis and luciferase reporter gene assays revealed that Kruppel-like factor 7 (KLF7) was the target of miR-185. Overexpression of miR-185 reduced the expression of KLF7 in NSCLC cells. Upregulation of KLF7 partly neutralized the inhibitory effects of miR-185 on the proliferation and invasion of NSCLC. Additionally, we confirmed that miR-185 suppressed the tumor growth of NSCLC A549 cells in vivo. Taken together, these results demonstrate that miR-185 acts as a suppressor by targeting KLF7 in NSCLC.

Key words: miR-185; Non-small cell lung cancer (NSCLC); KLF7; Metastasis

High Blood miR-802 Is Associated With Poor Prognosis in HCC Patients by Regulating DNA Damage Response 1 (REDD1)-Mediated Function of T Cells – 1025
DOI: https://doi.org/10.3727/096504018X15456687424096

Chao Jiang,* Xueyan Liu,† Meng Wang,* Guoyue Lv,* and Guangyi Wang*

*Department of Hepatobiliary Pancreatic Surgery, First Hospital of Jilin University, Changchun, P.R. China
†Department of Cardiology, China–Japan Union Hospital of Jilin University, Changchun, P.R. China

miR-802 has been reported to be dysregulated in multiple tumors and contribute to tumor progression. However, its role in HCC was still largely unknown. The aim of this study is to investigate the function and mechanism of miR-802 in HCC progression. The results showed that miR-802 was upregulated in the peripheral blood and tumor tissue of HCC patients, and high levels of blood miR-802 predicted poor prognosis. miR-802 had no effect on the proliferation and migration of HCC cell lines. Interestingly, the levels of CD8/CD28 and regulated in development and DNA damage response 1 (REDD1) were declined along with the upregulation of miR-802 in vivo. Hence, it is speculated that miR-802 participated in the regulation of T-cell function in HCC patients. Furthermore, we demonstrated that mir-802 directly targets REDD1 and inhibited its expression. miR-802 increased the expression of programmed cell death protein 1 (PD-1) and decreased the expression of interferon-γ (IFN-γ) and CD8⁺CD28⁺ T-cell number. In conclusion, miR-802 was involved in T-cell exhaustion through posttranscriptionally suppressing REDD1, which might offer the suppressive effect of miR-802 on HCC progression.

Key words: Hepatocellular carcinoma (HCC); REDD1; Programmed cell death protein 1 (PD-1); miR-802; T-cell exhaustion

MicroRNA-204 Potentiates the Sensitivity of Acute Myeloid Leukemia Cells to Arsenic Trioxide – 1035
DOI: https://doi.org/10.3727/096504019X15528367532612

Zhiguo Wang,*† Zehui Fang,‡ Runzhang Lu,† Hongli Zhao,‡ Tiejun Gong,† Dong Liu,† Luojia Hong,‡ Jun Ma,† and Mei Zhang*

*Department of Hematology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shanxi Province, P.R. China
†Department of Bone Marrow Transplantation, Harbin Hematological Cancer Institute, Harbin the First Hospital, Harbin Province, P.R. China
‡Department of Endocrinology, the 4th Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, P.R. China

Although arsenic trioxide (ATO) is a well-known antileukemic drug used for acute promyelocytic leukemia treatment, the development of ATO resistance is still a big challenge. We previously reported that microRNA-204 (miR-204) was involved in the regulation of acute myeloid leukemia (AML) cell apoptosis, but its role in chemoresistance is poorly understood. In the present study, we showed that miR-204 was significantly increased in AML cells after ATO treatment. Interestingly, the increased miR-204 level that was negatively correlated with ATO induced the decrease in cell viability and baculoviral inhibition of apoptosis protein repeat-containing 6 (BIRC6) expression. Overexpression of miR-204 potentiated ATO-induced AML cell growth inhibition and apoptosis. Furthermore, miR-204 directly targets to the 3′-UTR of BIRC6. Upregulation of miR-204 decreased BIRC6 luciferase activity and expression, which subsequently enhanced the expression of p53. Restoration of BIRC6 markedly reversed the effect of miR-204 on the regulation of AML cell sensitivity to ATO. Taken together, our study demonstrates that miR-204 decreases ATO chemoresistance in AML cells at least partially via promoting BIRC6/p53-mediated apoptosis. miR-204 represents a novel target of ATO, and upregulation of miR-204 may be a useful strategy to improve the efficacy of ATO in AML treatment.

Key words: Acute myeloid leukemia (AML); Arsenic trioxide (ATO); miR-204; Apoptosis; BIRC6

Triptolide Inhibits Breast Cancer Cell Metastasis Through Inducing the Expression of miR-146a, a Negative Regulator of Rho GTPase – 1043
DOI: https://doi.org/10.3727/096504019X15560124931900

Qin Liu,*† Wei Wang,† Fangqiong Li,† Dongyang Yu,‡ Chunfen Xu,* and Hongbing Hu*

*Department of Blood Transfusion, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
†Department of Clinic Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou, P.R. China
‡Department of Clinic Laboratory, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China

Triptolide, an extract of Tripterygium wilfordii, has been shown to have a potent anticancer activity. In the present study, it was found that triptolide could effectively induce apoptosis and inhibit proliferation and invasion in malignant MDA-MB-231 breast cancer cells. The study focused on its effect on inhibiting invasion, which has not been extensively reported to date. We predicted that triptolide may change invasion activity via microRNAs (miRNAs), which have been recognized as important regulators of gene expression. miRNAome variation in MDA-MB-231 cells with or without triptolide treatment demonstrated that miR-146a was upregulated following treatment with triptolide. Our previous studies have shown that miR-146a can inhibit migration and invasion by targeting RhoA in breast cancer. This time, we found that miR-146a can target Rac1, another key member of the Rho GTPase family. Luciferase reporter containing Rac1 3′-UTR was constructed to prove this hypothesis. In addition, following treatment with triptolide, the expression of RhoA and Rac1 was found to be decreased. These results indicated that triptolide exerts its anti-invasion activity through a miRNA-mediated mechanism, which indirectly regulates the expression of Rho GTPase. Triptolide combined with miR-146a could improve the effect of triptolide treatment on breast cancer.

Key words: Breast cancer; Triptolide; miR-146a; Rho A; Rac1

CRISPR/Cas9-Mediated Gene Knockout of ARID1A Promotes Primary Progesterone Resistance by Downregulating Progesterone Receptor B in Endometrial Cancer Cells – 1051
DOI: https://doi.org/10.3727/096504019X15561873320465

Haizhen Wang,* Zhenghua Tang,* Ting Li,* Menglu Liu,* Yong Li,† and Baoling Xing*

*Department of Pathology, Changzhou Maternal and Child Health Hospital Affiliated to Nangjing Medical University, Changzhou, P.R. China
†Department of Gynecology, Changzhou Maternal and Child Health Hospital Affiliated to Nangjing Medical University, Changzhou, P.R. China

Medroxyprogesterone (MPA) is used for the conservative treatment of endometrial cancer. Unfortunately, progesterone resistance seriously affects its therapeutic effect. The purpose of the current study was to investigate the influence of deletion of AT-rich interactive domain 1A (ARID1A) in progesterone resistance in Ishikawa cells. Ablation of ARID1A was conducted through the CRISPR/Cas9 technology. Acquired progesterone-resistant Ishikawa (Ishikawa-PR) cells were generated by chronic exposure of Ishikawa cells to MPA. The sensitivity of the parental Ishikawa, Ishikawa-PR, and ARID1A-deficient cells to MPA and/or LY294002 was determined using the Cell Counting Kit-8 (CCK-8) assay and flow cytometry analysis. In addition, Western blot analysis and reverse transcription-polymerase chain reaction was performed to evaluate the mRNA and protein expression levels of ARID1A, progesterone receptor B (PRB), and P-AKT. Both Ishikawa-PR and ARID1A knockout cells showed insensitivity to MPA, downregulation of PRB, and hyperphosphorylation of AKT compared to the parental Ishikawa cells. Pretreatment with LY294002 significantly enhanced the ability of MPA to suppress proliferation and to induce apoptosis in the parental and Ishikawa-PR cells via the inhibition of AKT activation and upregulation of PRB transcriptional activity. However, the PRB transcriptional activity and insensitivity to MPA were irreversible by LY294002 in ARID1A-deficient cells. Ablation of ARID1A is associated with low PRB expression, which serves an important role in primary progesterone resistance. Akt inhibition cannot rescue PRB or sensitize to MPA in ARID1A knockout cells. These findings suggest that ARID1A may act as a reliable biomarker to predict the response for the combination of AKT inhibitor and MPA treatment.

Key words: Endometrial cancer; Progesterone resistance; AT-rich interactive domain 1A (ARID1A); Progesterone receptor B (PRB); PI3K/AKT pathway

miR-186 Suppresses the Progression of Cholangiocarcinoma Cells Through Inhibition of Twist1 – 1061
DOI: https://doi.org/10.3727/096504019X15565325878380

Ming Zhang, Baochang Shi, and Kai Zhang

Department of Hepatobiliary Surgery, Shandong Provincial Third Hospital, Jinan, Shandong, P.R. China

Deregulation of miR-186 and Twist1 has been identified to be involved in the progression of multiple cancers. However, the detailed molecular mechanisms underlying miR-186-involved cholangiocarcinoma (CCA) are still unknown. In this study, we found that miR-186 was downregulated in CCA tissues and cell lines, and negatively correlated with the expression of Twist1 protein. In vitro assays demonstrated that miR-186 mimics repressed cell proliferation, in vivo tumor formation, and caused cell cycle arrest. miR-186 mimics also inhibited the migration and invasion of CCLP1 and SG-231 cells. Mechanistically, the 3′-untranslated region (3′-UTR) of Twist1 mRNA is a direct target of miR-186. Further, miR-186 inhibited the expressions of Twist1, N-cadherin, vimentin, and matrix metallopeptidase 9 (MMP9) proteins, whereas it increased the expression of E-cadherin in CCLP1 and SG-231 cells. Silencing of Twist1 expression enhanced the inhibitory effects of miR-186 on the proliferation, migration, and invasion of CCLP1 and SG-231 cells. In conclusion, miR-186 inhibited cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) through targeting Twist1 in human CCA. Thus, miR-186/Twist1 axis may benefit the development of therapies for CCA.

Key words: miR-186; Cholangiocarcinoma (CCA); Twist1; E-cadherin

Reactive Oxygen Species-Mediated Cezanne Inactivation by Oxidation of its Catalytic Cysteine Residue in Hepatocellular Carcinoma – 1069
DOI: https://doi.org/10.3727/096504019X15566157027506

Zhongyuan Yin,* Lin Yang,† Feng Wu,‡ Jinshuo Fan,‡ Juanjuan Xu,‡ Yang Jin,‡ and Guanghai Yang§

*Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
†Oncology Department, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
‡Department of Respiratory Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
§Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China

Cysteine oxidation occurs at the active site of deubiquitinases (DUBs) during many biologic signaling cascades. Here we report that hepatocellular carcinoma cells (HCCs) generated higher levels of endogenous reactive oxygen species (ROS). This elevated ROS production was inhibited by NADPH oxidase inhibitor diphenylene iodonium (DPI) and mitochondria electron chain inhibitor rotenone in HCC cells. Moreover, we found that H2O2 could activate NF-κB-dependent inflammatory effect through increased induction of matrix metalloproteinase 2 (MMP2), MMP9, and intercellular adhesion molecule 1 (ICAM1) expression levels. In addition, we found that H₂O₂ could prolong NF-κB activation by suppressing the negative regulatory functions of Cezanne in HCC cells. Ubiquitin-derived thiol-reactive probe (HA-UbVME) assay and biotin-tagged 1,3-cyclohexadione derivative (DCP-Bio1) assay showed that H₂O₂ has the capacity to inhibit the catalytic activity of Cezanne, and the reducing agent, DTT, could reactivate the Cezanne deubiquitinating enzyme activity. Taken all together, these findings demonstrated an important role for oxidation of Cezanne by ROS in regulation of the inflammatory effect of hepatocellular carcinoma.

Key words: Cezanne; Cysteine oxidation; Hepatocellular carcinoma (HCC)

Profilin 2 Promotes Proliferation and Metastasis of Head and Neck Cancer Cells by Regulating PI3K/AKT/β-Catenin Signaling Pathway – 1079
DOI: https://doi.org/10.3727/096504019X15579146061957

Kecheng Zhou,*†1 Jie Chen,*†1 Jiayu Wu,*†1 Yangxinzi Xu,‡ Qiaoyun Wu,*† Jingjing Yue,*† Yu Song,§ Shengcun Li,*† Peng Zhou,¶ Wenzhan Tu,*† Guanhu Yang,*† and Songhe Jiang*†

*Department of Physical Medicine and Rehabilitation, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China
†Integrative and Optimized Medicine Research Center, China–USA Institute for Acupuncture and Rehabilitation, Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China
‡Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada
§Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui, P.R. China
¶Department of Anatomy, Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China

Profilin 2 (PFN2) was found to be mainly expressed in neurons and involved in the development of the brain. In recent years, emerging evidence indicated that PFN2 is also significantly upregulated in various cancers including head and neck cancer (HNSC) and influences cancer cell proliferation, migration, and invasion. However, the role of PFN2 in HNSC development and progression remains unclear. The aim of our study was to investigate the role of PFN2 in the development of HNSC and its possible molecular mechanisms. Bioinformatics showed that increased expression of PFN2 in tumors correlated highly with poor prognosis of HNSC patients. Our results indicated that PFN2 was highly expressed in HNSC tissues and in HNSC cell lines. Knockdown of PFN2 inhibited proliferation, invasion, and migration of HNSC cells, while PFN2 overexpression produced the opposite effects. Using a nude mouse xenograft model, we substantiated the tumor-promoting effect of PFN2 on HNSC in vivo. Furthermore, we found that PFN2 downregulation reduced the phosphorylation of Akt and GSK-3β and reduced the expression of β-catenin in HNSC cells. The opposite was observed when PFN2 was overexpressed. Collectively, these results suggest that PFN2 promotes the proliferation and metastasis of HNSC by activating the PI3K/Akt/β-catenin signaling pathway. Although further validation is needed, we speculate that PFN2 plays a crucial role in HNSC and may be a promising therapeutic target and prognostic biomarker.

Key words: Head and neck cancer (HNSC); Profilin 2 (PFN2); Proliferation; Migration; Invasion; PI3K/Akt/β-catenin pathway

Volume 27 Subject and Author Index  – 1089

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