Abstract:
:Development of targeted therapeutics is still at its early stage for hepatocellular carcinoma (HCC) due to the incomplete understanding of the confounding regulations at signaling pathway level. In this investigation, gene co-expression-based networking and integrative functional genomic modeling of HCC mRNA profiles as signaling processes were employed to understand the complex signaling cascades involved in HCC development toward understanding the avenues for targeted therapeutics. Multiple sets of genes and molecular biological processes involved during HCC development were identified from this integrative analysis: (i) Loss of liver cellular features due to the reduced HNF4A & PPAR signaling in the early stages of HCC, (ii) activated inflammatory and stress signals in the cirrhosis stages and (iii) highly activated cellular proliferation with the activated E2F-MYC oncogenic signaling with the gain of embryonic liver stem cell-like features in the advanced stage tumors. Upon connecting these gene-sets with the established drug sensitivity-related gene signatures, targeted therapeutic strategies for the heterogeneous HCC conditions have been identified. PPAR agonist class of drugs for early stage HCC conditions, anti-inflammatory drugs for cirrhosis and topoisomerase inhibitors for the advanced HCC conditions were inferred. Integrative functional genomic analysis of HCC transcriptome profiles at the context of signaling pathways has defined the key molecular processes involved in HCC development. Further, the study highlights the stage-specific and pathway focused targeted therapeutics for HCC. These findings deserve extensive preclinical explorations toward the establishment of targeted therapeutics.
journal_name
Int J Cancerjournal_title
International journal of cancerauthors
Ramesh V,Ganesan Kdoi
10.1002/ijc.30195subject
Has Abstractpub_date
2016-10-01 00:00:00pages
1586-97issue
7eissn
0020-7136issn
1097-0215journal_volume
139pub_type
杂志文章abstract::Cells from reticulum-cell sarcomas (RCS), tumors with a probable B-cell origin in the SJL/J mouse strain, induced a high degree of proliferation in O-bearing syngeneic lymph-node and thymus cells obtained from young non-tumours mice. Although of considerably lower magnitude, a proliferation of SJL/J thymus cells to sy...
journal_title:International journal of cancer
pub_type: 杂志文章
doi:10.1002/ijc.2910140615
更新日期:1974-12-15 00:00:00
abstract::An Epstein-Barr virus-related herpesvirus, termed Herpesvirus papio (HVP), was isolated from baboons (Papio hamadryas) at the Institute of Experimental Pathology and Therapy, Sukhumi, USSR, where there is a continuing outbreak of lymphoma. In the present study sera from diseased baboons and from age- and sex-matched c...
journal_title:International journal of cancer
pub_type: 杂志文章
doi:10.1002/ijc.2910230208
更新日期:1979-02-01 00:00:00
abstract::Previous studies have proved that a certain acidic isoform of ferritin is specifically synthesized by the placenta and breast-cancer tissue. In this context it has been further reported that the determination of this so-called placental isoferritin (PLF) on the surface of a subset of peripheral lymphocytes is highly s...
journal_title:International journal of cancer
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doi:10.1002/ijc.2910520213
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abstract::Alterations in the gene copy numbers of the proto-oncogenes HER2/neu and c-myc in primary human breast cancer investigated in 73 patients. We detected amplification of HER2/neu in 17 patient samples and amplification of c-myc in 11, while amplification of both was seen in 6 samples. There was no correlation of age, ho...
journal_title:International journal of cancer
pub_type: 杂志文章,评审
doi:10.1002/ijc.2910430218
更新日期:1989-02-15 00:00:00
abstract::MUC18/MCAM is a cell-surface glycoprotein that is strongly expressed on advanced human melanomas. Transfection of 3 MCAM-negative melanoma cell lines with MCAM cDNA led to cell-surface expression and to a MCAM-dependent homotypic adhesion. This adhesion was independent of divalent cations and was inhibited at 4 degree...
journal_title:International journal of cancer
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更新日期:1997-11-27 00:00:00
abstract::Two genes encoding the latent membrane protein 1 (LMP1) of the Epstein-Barr virus (EBV) were isolated from a single case of Hodgkin's disease (HD) and were tested for their biological activities. The LMP1 gene from the Reed-Sternberg cells contained point mutations relative to the prototype LMP1 gene, leading to amino...
journal_title:International journal of cancer
pub_type: 杂志文章
doi:10.1002/(sici)1097-0215(19980413)76:2<194::aid-ijc
更新日期:1998-04-13 00:00:00
abstract::Urinary bladder cancer is a heterogeneous disease with tumors ranging from papillary noninvasive (stage Ta) to solid muscle infiltrating tumors (stage T2+). The risk of progression and death for the most frequent diagnosed type, Ta, is low, but the high incidence of recurrences has a significant effect on the patients...
journal_title:International journal of cancer
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更新日期:2010-03-15 00:00:00
abstract::We have employed the DNA-mediated gene transfer method to introduce the allogenic major-histocompatibility-complex(MHC)-class-I gene H-2Kb into the K36.16 tumor cells, H-2k, in order to generate tumor-specific immunity. The acquisition of immunogenicity by the H-2Kb-transformed clones following gene transfer is associ...
journal_title:International journal of cancer
pub_type: 杂志文章
doi:10.1002/ijc.2910570215
更新日期:1994-04-15 00:00:00
abstract::Although thyroid cancer is suspected to have a nutritional etiology, prospective studies examining the relationship between diet and thyroid cancer are lacking. During 1996-1997, NIH-AARP Diet and Health Study participants, ages 51-72 years, completed a 37-item food frequency questionnaire about diet at ages 12-13 yea...
journal_title:International journal of cancer
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doi:10.1002/ijc.29600
更新日期:2015-11-15 00:00:00
abstract::We report here side population (SP) cells, a cancer stem cell enriched fraction from pancreatic cancer cell line, have enormous superior potential of the epithelial to mesenchymal transition (EMT), invasion, and metastasis. In an isolated SP cell culture, the cells rapidly expressed and up-regulated E-cadherin, an epi...
journal_title:International journal of cancer
pub_type: 杂志文章
doi:10.1002/ijc.24349
更新日期:2009-06-15 00:00:00
abstract::The LIM 1863 colon carcinoma cell line grows in the form of morphologically and functionally organized organoids. Cells are arranged around a central lumen with a brush border and nuclei are polarized to the periphery. The organoids contain 3 morphological cell types (columnar, goblet and caveolated cells). By agar cl...
journal_title:International journal of cancer
pub_type: 杂志文章
doi:10.1002/ijc.2910500515
更新日期:1992-03-12 00:00:00
abstract::In advanced cancer patients, the oxidative stress could take place either at the onset of disease or as a function of disease progression. To test this hypothesis, the following parameters were investigated: the erythrocyte activity of the enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx), the serum ...
journal_title:International journal of cancer
pub_type: 杂志文章
doi:10.1002/ijc.10143
更新日期:2002-03-01 00:00:00
abstract::The current paradigm stipulates that inhibition of histone deacetylase (HDAC) 6 is essential for the combinatorial effect of proteasome and HDAC inhibitors for the treatment of cancers. Our study aims to investigate the effect of combining different class I HDAC inhibitors (without HDAC6 action) with a proteasome inhi...
journal_title:International journal of cancer
pub_type: 杂志文章
doi:10.1002/ijc.28924
更新日期:2014-12-15 00:00:00
abstract::Beta-lapachone and camptothecin are structurally unrelated agents thought to inhibit topoisomerase-I activity through distinct mechanisms. We find that beta-lapachone is much more potent than camptothecin in inducing acute cytotoxic effects on human malignant glioma cells. Acute cytotoxicity induced by both drugs is a...
journal_title:International journal of cancer
pub_type: 杂志文章
doi:10.1002/(sici)1097-0215(19971127)73:5<707::aid-ijc
更新日期:1997-11-27 00:00:00
abstract::The cell-cycle regulator p16 inhibits the complex cdk4-cyclin D1 and controls G1-S transition. In human tumors, p16 inactivation is often accomplished by homozygous deletion (HD) of its encoding gene, CDKN2A. Methylation of the 5' CpG island promoter has been proposed as an alternative mechanism of inactivation. Expre...
journal_title:International journal of cancer
pub_type: 杂志文章
doi:10.1002/1097-0215(20001115)88:4<554::aid-ijc6>3.0.
更新日期:2000-11-15 00:00:00
abstract::Breast cancer is heterogeneous in clinical behavior by subtypes; however, it is unclear how this heterogeneity is related to epidemiological factors. To evaluate the differences in epidemiological factors by breast tumor subtypes, we investigated the associations of epidemiological factors between tumor subtypes in Ko...
journal_title:International journal of cancer
pub_type: 杂志文章,多中心研究
doi:10.1002/ijc.28685
更新日期:2014-08-01 00:00:00
abstract::The role of IL-33/ST2 pathway in antitumor immunity is unclear. Using 4T1 breast cancer model we demonstrate time-dependent increase of endogenous IL-33 at both the mRNA and protein levels in primary tumors and metastatic lungs during cancer progression. Administration of IL-33 accelerated tumor growth and development...
journal_title:International journal of cancer
pub_type: 杂志文章
doi:10.1002/ijc.28481
更新日期:2014-04-01 00:00:00
abstract::Signal transduction pathways controlling tumor cell locomotion are not yet well understood. We have studied the role of protein kinase C (PKC)-dependent protein phosphorylation associated with changes in cell shape and locomotor activity of Walker carcinosarcoma cells in culture. We show that the inhibitory effect of ...
journal_title:International journal of cancer
pub_type: 杂志文章
doi:10.1002/(SICI)1097-0215(19960208)65:4<473::AID-IJC
更新日期:1996-02-08 00:00:00
abstract::Suramin is an experimental anti-neoplastic agent which has shown promising activity against prostatic carcinoma and lymphoma in clinical trials. To elucidate its mechanism of action, suramin was examined for an effect on the transport of folate compounds by tumor cells. Influx of the anti-folate methotrexate via the r...
journal_title:International journal of cancer
pub_type: 杂志文章
doi:10.1002/ijc.2910610616
更新日期:1995-06-09 00:00:00
abstract::We assessed whether split dosing with the methylating agent DTIC is an effective strategy for inactivating the DNA repair protein O6-alkylguanine DNA-ATase in order to decrease tumour resistance to BCNU. ATase levels in PBMCs were used as a surrogate for tumour ATase depletion to determine whether this correlated with...
journal_title:International journal of cancer
pub_type: 杂志文章
doi:10.1002/ijc.10849
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abstract::Incidence data pertaining to more than 250,000 cancer cases diagnosed during the years 1972-1989 among residents of urban Shanghai, China, were analyzed to determine the relative importance of the various malignancies and to discover changes over time. In the most recent 3-year period, lung cancer was the most frequen...
journal_title:International journal of cancer
pub_type: 杂志文章
doi:10.1002/ijc.2910530510
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abstract::Using comparative genomic hybridisation, we investigated chromosomal imbalances in 28 cases of thymic epithelial neoplasms including type A, B2, B3, the A component of type AB and different subtypes of type C thymoma. To identify different patterns of chromosomal aberrations associated with the biological behaviour an...
journal_title:International journal of cancer
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更新日期:2003-07-01 00:00:00
abstract::This report describes the appearance of ectopic chromosome around centrosome (ECAC) in metaphase cell nuclei of high-risk HPV-associated cervical neoplasms. ECAC are clearly visible on HE-stained sections as a tiny (approx. 0.7 micro), round, dark structure or an aggregate of filamentous chromosome, often symmetrical ...
journal_title:International journal of cancer
pub_type: 杂志文章,多中心研究
doi:10.1002/ijc.11216
更新日期:2003-08-20 00:00:00
abstract::Human papillomavirus (HPV) infections and HPV-associated penile lesions are frequently found in male sexual partners of women with cervical intraepithelial neoplasia (CIN). To determine the significance of these findings, we studied the prevalence of HPV and HPV associated penile lesions in a male hospital population ...
journal_title:International journal of cancer
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doi:10.1002/ijc.20502
更新日期:2005-01-01 00:00:00
abstract::Use of hormone replacement therapy (HRT) has been hypothesized to affect survival of epithelial ovarian cancer (EOC). We studied 5-year survival in patients with invasive EOC and borderline ovarian tumors (BOT) according to HRT use before and after diagnosis in a prospective nation-wide cohort study of 799 women diagn...
journal_title:International journal of cancer
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abstract::Previous studies have revealed a robust association between exposure to asbestos and human lung cancer. Accumulating evidence has highlighted the role of epigenome deregulation in the mechanism of carcinogen-induced malignancies. We examined the impact of asbestos on DNA methylation. Our genome-wide studies (using Ill...
journal_title:International journal of cancer
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abstract::Fibroblast growth factor 15 (FGF15), FGF19 in humans, is a gut-derived hormone and a key regulator of bile acids and carbohydrate metabolism. FGF15 also participates in liver regeneration after partial hepatectomy inducing hepatocellular proliferation. FGF19 is overexpressed in a significant proportion of human hepato...
journal_title:International journal of cancer
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abstract::Renewed interest in the use of therapeutic enzymes combined with an improved knowledge of cancer cell metabolism, has led to the translation of several arginine depletion strategies into early phase clinical trials. Arginine auxotrophic tumors are reliant on extracellular arginine, due to the downregulation of arginos...
journal_title:International journal of cancer
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abstract::A panel of monoclonal antibodies (MAbs) has been obtained, directed against determinants of normal human colorectal epithelium. BALB/c mice were immunized and boosted with mucosal scrapings and cell membrane preparations from normal large intestine. In one case boosting was also performed with HT29 colon carcinoma cel...
journal_title:International journal of cancer
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doi:10.1002/ijc.2910390309
更新日期:1987-03-15 00:00:00
abstract::Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit proliferation and angiogenesis in colorectal cancer. We examined a possible involvement of store-operated calcium (SOC) entry in human colon carcinoma cells (HRT-18), which require calcium for proliferation. Acetyl-salicylic-acid (ASA), mefenamic acid (MEF) and su...
journal_title:International journal of cancer
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doi:10.1002/ijc.1280
更新日期:2001-06-15 00:00:00