ISSN: 1948-5956
Journal of Cancer Science & Therapy
Like us on:
Make the best use of Scientific Research and information from our 700+ peer reviewed, Open Access Journals that operates with the help of 50,000+ Editorial Board Members and esteemed reviewers and 1000+ Scientific associations in Medical, Clinical, Pharmaceutical, Engineering, Technology and Management Fields.
Meet Inspiring Speakers and Experts at our 3000+ Global Conferenceseries Events with over 600+ Conferences, 1200+ Symposiums and 1200+ Workshops on
Medical, Pharma, Engineering, Science, Technology and Business

The Regucalcin Gene is a Key in the Therapy of Hepatocellular Carcinoma

Masayoshi Yamaguchi*
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, USA
Corresponding Author : Masayoshi Yamaguchi, PhD
Department of Hematology and Medical Oncology
Emory University School of Medicine
1365 C Clifton Road, NE, Atlanta, GA 30322, USA
Received January 20, 2014; Accepted January 23, 2014; Published January 27, 2014
Citation: Yamaguchi M (2014) The Regucalcin Gene is a Key in the Therapy of Hepatocellular Carcinoma. J Cancer Sci Ther 6:e132. doi:10.4172/1948-5956.1000e132
Copyright: © 2014 Yamaguchi M. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Related article at
DownloadPubmed DownloadScholar Google

Visit for more related articles at Journal of Cancer Science & Therapy

Hepatocellular carcinoma (HCC), the most common primary liver cancer, is one of the most prevalent malignant diseases worldwide, and the third most common causes of cancer-related death [1-3]. Globally, there are approximately 750,000 new cases of HCC reported per year. The incidence of HCC is increasingly in the United States and other developed countries. Moreover, features of HCC are an aggressive cancer with a dismal outcome largely due to metastasis and postsurgical recurrence. In most cases, HCC originates on a background of cirrhosis, a chronic and diffuse hepatic disease that result from continuous liver injury and regeneration [3]. Cirrhosis is present in approximately 80%- 90% of HCC patients and constitutes the largest single risk factor. In cirrhotic liver, changes in fat metabolism associated with the activation of adipocyte-like pathways are thought to be involved in neoplastic transformation [3]. Increased hepatocyte turnover, inflammation, and oxidative DNA damage is implicated in the pathogenesis of the liver disease including obesity, Type 2 diabetes, insulin resistant, and nonalcoholic fatty liver disease. The prevalent risk factors for HCC are also the cause of liver cirrhosis, and include viral infections (hepatitis B and C) and alcohol consumption; further risk factors include tobacco smoking, exposure to aflatoxin B1 and vinyl chloride, diabetes, and genetic disorders, such as hemochromatosis and alpha-1 antitrypsin deficiency [4-8].
Hepatocarcinogenesis is a multistep process initiated by external stimuli that lead to genetic changes in hepatocytes or stem cells, resulting in proliferation, apoptosis, dysplasia and neoplasia. The majority of HCC cases are also related to chronic viral infections. Hepatitis B virus (HBV) DNA integrates into the host genome, inducing chromosome instability and insertional mutations that may activate various oncogenes, such as cyclin A [9-12]. Viral proteins, in particular X protein (HBx), act as transactivators to upregulate several oncogenes (such as c-myc and c-jun) and transcriptional factors (such as nuclear factor-κB) [13-15]. Additionally, HBx activates promoters of genes encoding interleukin-8 (IL-8), tumor necrosis factor (TNF), transforming growth factor (TGF)-β and epidermal growth factor receptor (EGFR) [16]. HBx can also stimulate several signal transduction pathways, including the JAK/STAT, RAS/RAF/MAPK, and Wnt/β-catenin pathways [16,17]. The contributions of hepatitis C virus (HCV) to hepatocarcinogenesis are mediated through viral proteins, including core, NS3 and NS5A proteins. HCV core protein can promote apoptosis or cell proliferation through interaction with p53 or upregulation of Wnt-1 at the transcriptional level [18-20].
The prognosis of advanced HCC remains poor in spite of the development of novel therapeutic strategies [21]. Traditional therapies are not effective for HCC and are too toxic for patients with cirrhosis. Transarterial chemoembolization and radioembolization are the main treatments for intermediate-stage HCC at the present time. Improved knowledge of the oncogenic processes and signaling pathways that regulate tumor cell proliferation, differentiation, angiogenesis, invasion and metastatis has led to the identification of several potential therapeutic targets, which have driven the development of molecularly targeted therapies [21]. An ideal cancer target meets the following criteria: the target is relatively specific for cancer cells (not expressed or expressed at very low levels in normal cells but overexpressed in cancer cells) [21]. Meanwhile, overexpression of the target is associated with malignant biological phenotypes and/or poor prognosis; the target plays an essential role in cancer initiation and progression, and inhibition of expression or activity of the target induces growth suppression and/or apoptosis in cancer cells. The target is “drugable” as an enzyme (e.g., a kinase) or cell surface molecule (e.g., a membrane-bound receptor) that can be easily screened for small-molecule inhibitors or targeted by a specific antibody [21,22]. The only systemic therapy available for advanced HCC is based on the multikinase inhibitor sorafenib [22], which is the most effective therapeutic tool for advanced nonresectable HCC, in which it can slightly improve patient survival. The survival of patients with advanced HCC treated with sorafenib depends on the absence of liver dysfunction and on the status of the patient [23]. In the past few years, the use of sorafenib in combination with transarterial chemoembolization has improved survival rates in patients with advanced HCC. Recently, new perspectives in cancer treatment have appeared with the advent of microRNAs, a novel class of noncoding small RNAs [24].
Regucalcin, which the author discovered in 1978 [25-28], may play a pivotal role in the suppression of hepatocarcinogenesis [29-31]. Regucalcin plays a role as a suppressor protein in various cell signal transductions [26-28]. The regucalcin gene is located on the X chromosome in consisting of seven exons and six introns [32]. Regucalcin (RGN) and its gene (rgn) are identified in over 15 species consisting of regucalcin family and the gene species are highly conserved in vertebrate species [32]. The regucalcin gene expression is regulated through various transcription factors (including AP-1, NF1-A1, RGPR-p117, β-catenin, SP1 and others), which are identified as the enhancer and suppressor, and this expression is regulated with hormonal stimulation and physiological state [32]. Regucalcin plays a pivotal role as a suppressor protein in various signal transductions to maintain cell homeostasis for stimuli, and it plays a multifunctional role in cell regulation through maintaining of intracellular Ca2+ homeostasis and suppressing of signal transduction in various cell types [26-28]. Interestingly, the cytoplasmic regucalcin is translocated into the nucleus and inhibits nuclear Ca2+-dependent and -independent protein kinases and protein phosphatases, Ca2+-activated endonuclease, and DNA and RNA synthesis [33].
Regucalcin has been demonstrated to play a role as a suppressor protein in cell proliferation, which is mediated through various signaling stimulations, in the cloned normal rat kidney proximal tubular epithelial NRK52E cells and the cloned rat hepatoma H4-II-E cells [31,34,35]. Regucalcin causes G1 and G2/M phase cell cycle arrest in these cells [31,36]. The anti-cell proliferation effect of regucalcin is not dependent on apoptosis; regucalcin suppresses apoptosis induced through multisignaling pathway [37]. Molecular mechanisms by which regucalcin suppresses the promotion of cell proliferation have been elucidated. Regucalcin, which is expressed through signaling factors that stimulate cell proliferation, is translocated into the nucleus with mechanism by which is mediated through protein kinase C-dependent signaling [31,34]. Regucalcin directly inhibits the activities of various Ca2+/calmodulin-dependent enzymes, protein kinases and protein phosphatases in the cytoplasm and nuclei [27,28,31]. Regucalcin inhibits nuclear DNA and RNA synthesis, and it has suppressive effects on the expression of c-myc, Ha-ras, and c-src mRN, which are tumorstimulator genes and also stimulates the expression of p53 and Rb mRNAs that are tumor-suppressor genes [31,38]. Moreover, regucalcin inhibits protein synthesis and stimulates protein degradation due to inhibiting aminoacyl-tRNA synthetase and activating cysteinyl protease [27,28]. Thus, suppressive effects of regucalcin on cell proliferation are mediated through the suppression of many cell signaling processes including the suppression of oncogene expression and stimulation of tumor suppressor gene expression in liver cells [31,33,38].
Noticeably, the regucalcin gene and its protein levels have been found to specifically suppress in human hepatocellular carcinoma (HCC) using analysis with multiple gene expression profiles and proteomics [39-43]. The suppression of regucalcin gene expression has been shown to occur at earlier periods of carcinogenesis in rats treated with diethylnitrosamine and then 2-acetylaminofluorene combined with partial hepatectomy, which induces an increase in proliferating cells [29]. The suppression of regucalcin protein expression has also been identified in proteomic analysis that was differentially expressed in the livers of rats fed 5% ethanol for 1 and 3 months [30]. In addition, regucalcin mRNA expression is suppressed by disorder of liver metabolism (including carbon tetrachloride [44], galactosamine [45] and phenobarbital [46] administration, the conditions of diabetes and ethanol ingestion [47]), which may lead to cirrhosis and HCC. The suppression of regucalcin gene expression may lead to the development of HCC.
Regucalcin, a suppressor protein in cell signaling system, may play a role as a key molecule in the depression of cell proliferation and carcinogenesis of various tissues and cell types. Overexpression of regucalcin in cancer cells may play preventive and therapeutic roles in carcinogenesis. The development of a novel gene therapy with the regucalcin gene deliver system will be expected in clinical aspects.
Regucalcin studies of the author were supported by a Grant-in-Aid for Scientific Research (C) No.63571053, No.02671006, No.04671362, No.06672193, No.08672522, No.10672048, No.13672292 and No.17590063 from the Ministry of Education, Science, Sports, and Culture, Japan. Also, the author (MY) was awarded the Bounty of Encouragement Foundation in Pharmaceutical Research, Japan and the Bounty of the Yamanouchi Foundation for Research on Metabolic Disorders, Japan. This study was also supported by the Foundation for Biomedical Research on Regucalcin.

Select your language of interest to view the total content in your interested language
Share This Article
Relevant Topics
Disc Abnormal Pap Test
Disc Acute Lymphoblastic Leukemia
Disc Acute Megakaryocytic Leukemia
Disc Acute Myelomonocytic Leukemia
Disc Acute Myleoid Leukemia
Disc Adenocarcinoma pancreas
Disc Advances in Alternative Lung Cancer Treatment
Disc Advances in Breast Cancer Treatment
Disc Aleukemic Leukemia
Disc Alternative Treatments for Breast Cancer
Disc Anal Cancer Diagnosis
Disc Anti-Cancer Drug
Disc Apoptosis
Disc Bile Duct Cancer
Disc Biliary Cancer
Disc Bladder Cancer Diagnosis
Disc Blood Cancer Diagnosis
Disc Bone Cancer Stages
Disc Bone Marrow Cancer Survival
Disc Brain Cancer Diagnosis
Disc Brain Tumor Treatment
Disc Breast Cancer Biology
Disc Breast Cancer Cure
Disc Breast Cancer Diagnosis
Disc Breast Cancer Grading
Disc Breast Cancer Prevention
Disc Breast Cancer Radiotherapy
Disc Breast Cancer Research
Disc Breast Cancer Surgery
Disc Breast Cancer Therapeutic & Market Analysis
Disc Breast Screening
Disc Cancer Diagnosis
Disc Cancer Science
Disc Cancer Therapies
Disc Cancer initiation and progression
Disc Cancer therapy
Disc Carcinogenesis
Disc Carcinoid Tumours
Disc Cellular Oncology
Disc Cervical Biopsy
Disc Cervical Cancer Diagnosis
Disc Cervical Cancer Prevention
Disc Cervical Cancer Treatment
Disc Cervical Intra-epithelial Neoplasia (CIN)
Disc Cervical Screening
Disc Cervix-Cancer
Disc Chemo Resistance
Disc Chronic Lymphocytic Leukemia
Disc Chronic Myleloid Leukemia
Disc Clinical Oncology
Disc Colon Cancer Diagnosis
Disc Colon Cancer Surgery
Disc Colorectal Cancer
Disc Colposcopy
Disc Comparative Oncology
Disc Cone Biopsy
Disc DNA damage
Disc Dental Oncology
Disc Dermatologic Surgery
Disc Ductal adenocarcinoma
Disc Duodenal Cancer
Disc Electro Chemotherapy
Disc Esophageal Cancer
Disc Esophageal Cancer Diagnosis
Disc Feline Leukemia Complex
Disc Fibrocystic Breast
Disc Gall Bladder Cancer
Disc Gastro Intestinal Cancer Treatment
Disc Gastro Intestinal Stromal Tumours
Disc Gastroesophageal (GE) Junction Cancer
Disc Gastrointestinal Carcinoid Tumours
Disc Genital Warts
Disc Genitourinary Oncology
Disc Germ cell tumours
Disc Gynecological Cancers
Disc HPV Vaccination
Disc Hairy Cell Leukemia
Disc Hereditary Breast Cancer
Disc Human Immunodeficiency Virus (HIV)
Disc Human Papillomavirus (HPV)
Disc Inflammatory Breast Cancer
Disc Interventional Oncology
Disc Invasive Ductal Carcinoma
Disc Jaundice
Disc Kidney Cancer Diagnosis
Disc Kidney Cancer Prognosis
Disc Kidney Cancer Surgery
Disc Leukemia
Disc Leukemia Diagnosis
Disc Leukemia Drugs
Disc Leukemia Surgery
Disc Liver Cancer Diagnosis
Disc Lung Cancer Diagnosis
Disc Lung Cancer Surgery
Disc Lung Tumor
Disc Lungs Cancer Cure
Disc Lymph Node Cancer
Disc Lymphoma Cancer
Disc Lymphoma Diagnosis
Disc Lymphoma Surgery
Disc Lymphoma Symptoms
Disc Lymphomatous polyposis
Disc Lymphosarcoma
Disc Making Strides in Breast Cancer
Disc Mast Cell Leukemia
Disc Mastectomy
Disc Mesothelioma Diagnosis
Disc Metastatic Breast Cancer
Disc Molecular Oncology
Disc Mouth Cancer Diagnosis
Disc Musculoskeletal Oncology
Disc Mutagenesis
Disc Neurofibromatosis Type 1
Disc Oesophageal Cancer
Disc Oesophageal Cancer Surgery
Disc Oncology Analytics
Disc Oncology Emergency
Disc Oncology Esthetics
Disc Oncology Nutrition
Disc Oseophagus Cancer
Disc Ovarian Cancer Diagnosis
Disc Ovarian Cancer and Prognosis
Disc Pancreatic Cancer
Disc Pancreatic Cancer Diagnosis
Disc Pancreatic Cancer Surgery
Disc Pancreatic Islet Cell Cancer
Disc Papanicolaou Screening
Disc Pediatric Leukemia
Disc Photo carcinogenesis
Disc Plasma Cell Leukemia
Disc Prostate Cancer Diagnosis
Disc Prostate Cancer Surgery
Disc Radiation Therapy
Disc Radio Oncology
Disc Radiotherapy
Disc Radiotherapy for Breast Cancer
Disc Rectal Cancer Diagnosis
Disc Sarcoma Cancer
Disc Sexually Transmitted Disease (STD)
Disc Skin Cancer Diagnosis
Disc Skin Cancer Surgery
Disc Small Bowel Cancer
Disc Small Intestine Cancer
Disc Smoking in Breast Cancer
Disc Spleen Cancer
Disc Squamous Cell Cancer (SCC)
Disc Squamous Cell Carcinoma
Disc Stomach Cancer
Disc Stomach Cancer Surgery
Disc Terminal Breast Cancer
Disc Testicular Cancer Diagnosis
Disc Thoracic Oncology
Disc Throat Cancer Surgery
Disc Thyroid Cancer Diagnosis
Disc Thyroid Cancer Surgery
Disc Tumorigenesis
Disc Uterine Cancer Diagnosis
Disc Vaginal Oncology
Disc Venereal Disease
Disc Veterinary Oncology
Recommended Journals
Disc Gastrointestinal Cancer Journal
Disc Colorectal Cancer Journal
Disc Cervical Cancer Journal
Disc Breast Cancer Journal
Disc Cancer Surgery Journal
Disc Cancer Diagnosis Journal
Disc Leukemia Journal
Disc Integrative Oncology Journal
Disc Carcinogenesis & Mutagenesis Journal
Disc Chemotherapy Journal
  View More»
Recommended Conferences
Disc 11th Oncologists Meeting
July 11-13, 2016 Kuala Lumpur, Malaysia
Disc 10th Global Nursing & Healthcare Conference
August 18-20, 2016 São Paulo, Brazil
Disc 2nd World Congress on Breast Cancer
September 19-21, 2016 Phoenix, Arizona,USA
Disc Oncology Nursing Congress
September 19-21, 2016 Las Vegas, USA
Disc 12th Cancer Therapy Conference
September 26-28, 2016 London, UK
Disc 3rd World Congress on Women’s Health and Breast Cancer
October 03-05, 2016 London, UK
Disc 15th Euro Nursing & Medicare Summit
October 17-19, 2016 Rome, Italy
Disc 13th Cancer Therapy Summit
October 17-19, 2016 Dubai, UAE
Disc 6th Cancer Therapy Congress
December 01-03, 2016 Baltimore, USA
Disc 10th Nursing and Healthcare
December 05-07, 2016 Dallas, USA
Article Tools
Disc Export citation
Disc Share/Blog this article
Article usage
  Total views: 11203
  [From(publication date):
March-2014 - Jun 27, 2016]
  Breakdown by view type
  HTML page views : 7475
  PDF downloads :3728

Post your comment

captcha   Reload  Can't read the image? click here to refresh

OMICS International Journals
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
OMICS International Conferences 2016-17
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

Agri, Food, Aqua and Veterinary Science Journals

Dr. Krish

1-702-714-7001 Extn: 9040

Clinical and Biochemistry Journals

Datta A

1-702-714-7001Extn: 9037

Business & Management Journals


1-702-714-7001Extn: 9042

Chemical Engineering and Chemistry Journals

Gabriel Shaw

1-702-714-7001 Extn: 9040

Earth & Environmental Sciences

Katie Wilson

1-702-714-7001Extn: 9042

Engineering Journals

James Franklin

1-702-714-7001Extn: 9042

General Science and Health care Journals

Andrea Jason

1-702-714-7001Extn: 9043

Genetics and Molecular Biology Journals

Anna Melissa

1-702-714-7001 Extn: 9006

Immunology & Microbiology Journals

David Gorantl

1-702-714-7001Extn: 9014

Informatics Journals

Stephanie Skinner

1-702-714-7001Extn: 9039

Material Sciences Journals

Rachle Green

1-702-714-7001Extn: 9039

Mathematics and Physics Journals

Jim Willison

1-702-714-7001 Extn: 9042

Medical Journals

Nimmi Anna

1-702-714-7001 Extn: 9038

Neuroscience & Psychology Journals

Nathan T

1-702-714-7001Extn: 9041

Pharmaceutical Sciences Journals

John Behannon

1-702-714-7001Extn: 9007

Social & Political Science Journals

Steve Harry

1-702-714-7001 Extn: 9042

© 2008-2016 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version