Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. HCC occurs mainly in chronically diseased livers, e.g. following hepatitis B and C infection. These high-risk patients are closely followed up, and increasing numbers of small equivocal lesions are detected by imaging diagnosis. They are now widely recognized as precursor or early-stage HCCs and are classified as dysplastic nodule or early HCC. These lesions lack typical imaging and histology of ordinary HCC and do not show elevated serum markers of alpha-fetoprotein and PIVKA-II, for example. Molecular analysis of these lesions would help to develop molecular markers for objective histological diagnosis of early HCC and possibly new serum markers for early detection of HCC. It has been reported that HSP70, CAP2, glypican 3 and glutamine synthetase could serve as molecular markers for early HCC. Further analysis is expected to evaluate their usefulness in routine pathological diagnosis including biopsy diagnosis and also as serum markers for early detection of HCC.
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PMID:Candidate molecular markers for histological diagnosis of early hepatocellular carcinoma. 1854 47

Many studies have demonstrated that intracellular proteins, which are involved in carcinogenesis, can provoke autoantibody responses. Therefore, autoantibodies can be used clinically for cancer detection and for proteomic analysis in identification of tumor-associated antigens (TAAs) that are potentially involved in malignant transformation. Liver cancer, especially hepatocellular carcinoma (HCC), is one of the most common tumors in the world. The majority of people with HCC will die within 1 year of its detection. This high case fatality rate can partially be attributed to a lack of diagnostic methods that allow early detection. In the present study, sera from 20 patients with HCC, 30 patients with chronic hepatitis (CH), and 30 patients with liver cirrhosis (LC) as well as sera from 10 normal individuals were used in a proteomic approach to identify HCC-related TAAs. Thirty-four immunoreactive protein spots were excised from the two-dimensional gel electrophoresis (2DE), digested with trypsin, and subsequently analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Of 34 immunoreactive protein spots, 28 were identified. Seventeen of them were not only reactive with serum antibodies in HCC but also with antibodies in pre-HCC conditions, and 11 were only reactive with serum antibodies in HCC but not with antibodies in pre-HCC conditions. In the subsequent analysis, two representative proteins, HSP60 and HSP70, were selected as examples for the validation purpose. The results from immunoassay were consistent with the data from proteomic analysis, supporting our hypothesis that proteins identified with autoantibodies that have been present in precancer conditions may be not appropriate to use as TAA markers in cancer detection.
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PMID:Using proteomic approach to identify tumor-associated antigens as markers in hepatocellular carcinoma. 1867 25

The multistep process of hepatic carcinogenesis is mirrored by the morphologic classification of lesions detectable in cirrhosis, that include large regenerative nodules (LRN), low grade dysplastic nodules (LGDN) and high grade dysplastic nodules (HGDN). The latter belong to the "bordeline malignancy" cathegory requiring an accurate distinction from well-differentiated and early hepatocellular carcinoma. Nodules in cirrhosis are usually detected by non-invasive imaging techniques, being the latter unable to discriminate malignant from non-malignant forms, particularly in the 1-2 cm sized group. Liver biopsy is essential in providing practical diagnostic information to hepathologists in the management of cirrhotic patients with US detectable nodules. The histologic diagnosis on liver samples is based on the accurate search of a set of cyto-architectural features (cell atypia, cell crowding, trabecular thickness, microacini etc) and by a supplement of histochemical (Gomori staining) and immunocytochemical stainings. The latter rely upon the search of both well established and novel markers, targeted to evaluate stromal invasion (CK7/19), the vascular pattern (ASMA and CD34) or tumor markers (HSP70 and Glipican 3 among others). Still, the diagnostic sensitivity is limited by the type and size of sampling and by its representativity of the entire lesion. The best diagnostic approach thus requires the integration of clinical, morphological and immunocytochemical information with imaging data (US pattern, perfusional pattern, helical CT/MR pattern). Molecular data are still under evaluation as to their diagnostic efficacy in this controversial field. Discrepancies have emerged recently between Eastern and Western interpretation of these lesions, particularly in the cathegory of "borderline" nodules, that are mostly labelled as early, well differentiated HCC by eastern pathologists and as HGDN by western pathologists. Novel and more objective phenotypical and molecular markers are needed to discriminate within the grey area of borderline lesions that, epidemiologically, are likely distinct between eastern and western geographic areas. These tools might allow a better understanding of the boundaries of the process going from high grade dysplasia to in situ HCC and from the latter to microinvasive HCC and advanced HCC, for a proper clinical management and optimal therapy.
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PMID:Hepatocellular dysplastic nodules. 1872 69

The peptides mixture was prepared from tumor cells by freezingthawing cells, precipitation by heating, followed by acidification of the solution. The activation and proliferation of mouse splenocytes by HSP70-peptide complex, formed by the binding of HSP70 and peptides in vitro, were observed, so was the specific cytotoxicity of the proliferative lymphocytes to tumor cells. The phenotypes of the proliferative lymphocytes were analyzed by a flow cytometer. BALB/c mice inoculated with H22 hepatocarcinoma cells in peritoneal cavity or hind thigh were immunized by injection with HSP70-peptides complex to observe the inhibitory effect of the immunization on tumor and lifetime of tumor-bearing mice. On the other hand, blood samples were collected from the immunized mice to check the functions of liver and kidney. The results showed that the peptides mixture from tumor cells contained tumor-specific antigen peptides which could be presented by HSP70 to activate lymphocytes in vitro, the proliferative lymphocytes were T cells which were specifically cytotoxic to tumor cells, the in vivo growth of both ascitic and solid carcinoma could be suppressed by immunization with HSP70-peptides and the lifetime of tumor-bearing mice was prolonged, the in vivo immunization with HSP70-H22-peptides had no impact on the function of mouse liver and kidney, suggesting that there was no occurrence of autoimmunity in vivo after immunization.
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PMID:Investigation on the effect of peptides mixture from tumor cells inducing anti-tumor specific immune response. 1875 23

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. HCC occurs mainly in patients with chronic liver disease such as in hepatitis B and C infection. These high-risk patients are closely followed up, and increasing numbers of small equivocal lesions are detected by imaging diagnosis. They are now widely recognized as a precursor or early stage of HCC and are classified as dysplastic nodules or early HCC. It is considered that early HCC is a key step in the process of HCC development and progression. However, the molecular mechanisms of early hepatocarcinogenesis are far from clear. Specific mutations of classical oncogenes or tumor suppressor genes have not been identified in early HCC so far. Recent progress in comprehensive analysis of gene expression is shedding some light on this issue. It has been reported that HSP70, CAP2, glypican 3, and glutamine synthetase could serve as molecular markers for early HCC. Further analysis is expected to evaluate their usefulness in routine pathological diagnosis including biopsy diagnosis and also as serum markers for early detection of HCC.
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PMID:Early HCC: diagnosis and molecular markers. 1914 3

The heat shock (HS) response is a protective mechanism for cells to protect themselves against subsequent lethal stress. HS upregulated heat shock protein (HSP) expression reduced apoptosis following tumor necrosis factor-alpha (TNF-alpha) stimulation. However, vector-mediated overexpression of HSP70 failed to provide similar protection but rather sensitized cells to TNF-alpha induced apoptosis. This may be due to the fact that the kinetics of vector-mediated HSP overexpression is totally different from that of HSP upregulation by HS. We hypothesized that the response depends on the timing of TNF-alpha challenge relative to HSP expression dynamics after HS. Therefore, we investigated the correlation between the dynamic change of HSP expression and the levels of apoptosis induced by TNF-alpha after HS. Hepatoma cells were subjected to mild heat shock at 42 degrees C for 2 h followed by varied recovery times and then treated with TNF-alpha to induce apoptosis. The results from quantitative apoptosis assays using the TUNEL reaction reveal an optimal HS protection window centered around 5 h post-HS against TNF-alpha induced apoptosis. In addition, we found a window extending up to 2 h after HS where HS sensitized cells to TNF-alpha stress. Importantly, the correlation between apoptosis and HSP expression kinetics demonstrates that both high levels of HSPs and proper timing between HS and TNF-alpha stress were critical for optimal protection. Our study establishes a dynamic experimental model for further investigation of HS as a potential clinical approach to target tissue survival or death.
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PMID:Dynamic effect of heat shock pretreatment on apoptotic responses to TNF-alpha in liver cells. 1964 Jan 28

Recently, an East-West consensus on the histopathologic criteria for the diagnosis of high-grade dysplastic nodules (HGDN) versus early hepatocellular carcinoma (HCC) was reached. Next to classical morphologic criteria such as nucleocytoplasmic ratio, thickness of cell plates, mitotic index, and architectural disturbance like acinar structures, one of the most relevant criteria to diagnose early HCC is stromal invasion. Because a structured basement membrane is lacking along the hepatocytes in the liver, invasion cannot be defined as tumor growth through the basement membrane as in other tissues. However, the number of portal tracts that are present in a nodule gradually decrease because the tumoral hepatocytes start to show a destructive invading growth pattern in the mesenchyma/stroma of these portal tracts. This feature of stromal invasion is however sometimes difficult to recognize in needle biopsies because included portal tracts can be absent. Therefore, other diagnostic criteria are necessary. Based on molecular profiling, several additional markers for early malignant HCC have been found recently. Glypican-3, heat shock protein 70, and glutamine synthetase have been already validated and can be used as a panel of stains to confirm the pathologist's histopathologic diagnosis and to solve difficult cases.
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PMID:Pathology of early hepatocellular carcinoma: conventional and molecular diagnosis. 2017 30

Due to substantial technical improvements, clinical application of heat as a co-adjuvant in cancer treatment is acquiring new interest. The effect of hyperthermia on hepatoma cell lines Hep3B (p53 defective) and HepG2 (p53 wild type) when investigated led to an interesting observation that Hep3B cells are more susceptible to heat stress than HepG2 cells. In addition, heat-induced carboplatin resistance was observed in HepG2 cells only. To investigate the reasons, heat shock response was explored and it was observed that heat stress augmented heat shock protein 70 (Hsp70) expression levels in HepG2 and not in Hep3B cells. Furthermore, in HepG2 cells, induced Hsp70 is regulated by both p53 and heat shock transcription factor 1 (HSF1) wherein HSF1 levels are modulated by p53. The data implies that Hep3B are more susceptible to death upon heat stress than HepG2 cells because of non-induction of Hsp70. In addition, it was observed that inhibition of heat-induced p53/HSF1 diminishes Hsp70 levels, thereby restoring the sensitivity of heat-stressed HepG2 cells to carboplatin-triggered cell death. Collectively, the present study establishes interplay of p53, HSF1, and Hsp70 upon heat stress in HepG2 cells and also defines novel strategies to overcome constraints of utility of hyperthermia in cancer therapy through p53/HSF1-targeted therapeutic intervention.
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PMID:Hyperthermia-associated carboplatin resistance: differential role of p53, HSF1 and Hsp70 in hepatoma cells. 2018 Aug 6

Hepatocellular carcinoma (HCC) is the sixth most common malignancy and the third leading cause of cancer deaths worldwide. Proper classification and early identification of HCC and precursor lesions is essential to the successful treatment and survival of HCC patients. Recent molecular genetic, pathologic, and clinical data have led to the stratification of hepatic adenomas into three subgroups: those with mutant TCF1/HNF1 alpha gene, those with mutant beta-catenin, and those without mutations in either of these loci. Hepatic adenomas with alpha-catenin mutations have a significantly greater risk for malignant transformation in comparison with the other two subgroups. Telangiectatic focal nodular hyperplasia has now been reclassified as telangiectatic adenoma due to the presence of non-random methylation patterns, consistent with the monoclonal origin which is similar to hepatic adenoma and HCC. HCC precursor lesions demonstrate unique molecular alterations of HSP70, CAP2, glypican 3, and glutamine synthetase that have proven useful in the histologic diagnosis of early HCC. Though specific genetic alterations depend on HCC etiology, the main proteins affected include cell membrane receptors (in particular tyrosine kinase receptors) as well as proteins involved in cell signaling (specifically Wnt/beta-catenin, Ras/Raf/MEK/ERK and PI3K/Akt/mTOR pathways), cell cycle regulation (i.e. p53, p16/INK4, cyclin/cdk complex), invasiveness (EMT, TGF-beta) and DNA metabolism. Advances in gene expression profiling have provided new insights into the molecular genetics of HCC. HCCs can now be stratified into two clinically relevant groups: Class A, the low survival subclass (overall survival time 30.3+/- 8.02 months), shows strong expression signatures of cell proliferation and antiapoptosis genes (such as PNCA and cell cycle regulators CDK4, CCNB1, CCNA2, and CKS2) as well as genes involving ubiquitination and sumoylation; Class B, the high survival subclass (overall survival time 83.7 +/-10.3 months), does not have the above expression signature. In fact, insights into HCC-specific alterations of signal transduction pathways and protein expression patterns have led to the development of new therapeutic agents with molecular targets such as EGFR, VEGF, or other multi-kinase inhibitors. In the future, these specific molecular alterations in HCC can potentially serve as diagnostic tools, prognostic markers, and/or therapeutic targets with the potential to alter clinical outcomes.
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PMID:Molecular genetics of hepatocellular neoplasia. 2018 87

The study investigated the effects of heat shock protein 70 (HSP70) antisense oligonucleotide (ASODN) on the proliferation and apoptosis of a human hepatocellular carcinoma cell line (SMMC-7721 cells) in vitro. HSP70 oligonucleotide was transfected into SMMC-7721 cells by the mediation of Sofast transfection reagent. Inhibition rate of SMMC-7721 cells was determined by using MTT method. Apoptosis rate and cell cycle distribution were measured by flow cytometry. Immunocytochemistry staining was used to observe the expression of HSP70, Bcl-2 and Bax. The results showed that HSP70 ASODN at various concentrations could significantly inhibit the growth of SMMC-7721 cells, and the inhibition effect peaked 48 h after transfection with 400-nmol/L HSP70 ASODN. Cytometric analysis showed the apoptotic rate was increased in a dose- and time-dependent manner in the HSP70 ASODN-treated cells. The percentage of cells in the G2/M and S phases was significantly decreased and that in the G0/G1 phase increased as the HSP70 ASODN concentration was elevated and the exposure time prolonged. Immunocytochemistry showed that treatment of SMMC-7721 cells with HSP70 ASODN resulted in decreased expressions of HSP70 and Bcl-2 proteins, and an increased expression of Bax protein. It was concluded that the HSP70 ASODN can inhibit the growth of the SMMC-7721 cells and increase cell apoptosis by down-regulating the expression of HSP70. HSP70 ASODN holds promise for the treatment of hepatocellular carcinoma.
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PMID:Effects of HSP70 antisense oligonucleotide on the proliferation and apoptosis of human hepatocellular carcinoma cells. 2055 78


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