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)

The Ras gene product is a monomeric membrane-localized G protein of 21 kd that functions as a molecular switch linking receptor and nonreceptor tyrosine kinase activation to downstream cytoplasmic or nuclear events. Each mammalian cell contains at least three distinct ras proto-oncogenes encoding closely related, but distinct proteins. Activating mutations in these Ras proteins result in constitutive signaling, thereby stimulating cell proliferation and inhibiting apoptosis. Oncogenic mutations in the ras gene are present in approximately 30% of all human cancers. K-ras mutations occur frequently in non-small-cell lung, colorectal, and pancreatic carcinomas; H-ras mutations are common in bladder, kidney, and thyroid carcinomas; N-ras mutations are found in melanoma, hepatocellular carcinoma, and hematologic malignancies. The ras-signaling pathway has attracted considerable attention as a target for anticancer therapy because of its important role in carcinogenesis. In this review, the physiologic and biochemical properties of the Ras proteins, their mechanism of cell signaling, and their relation to human cancer will be discussed. Novel cancer therapeutic approaches based on the inhibition of Ras-mediated signaling, including inhibition of Ras processing, inhibition of Ras protein synthesis, and blockage of downstream Ras effectors, will be discussed.
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PMID:Blocking oncogenic Ras signaling for cancer therapy. 1209 90

Hepatocyte growth factor (HGF) induces growth stimulation of a variety of cell types, but it also induces growth inhibition of several types of tumor cell lines. The molecular mechanism of the HGF-induced growth inhibition of tumor cells remains obscure. We have investigated the intracellular signaling pathway involved in the antiproliferative effect of HGF on the human hepatocellular carcinoma cell line HepG2. HGF induced strong activation of ERK in HepG2 cells. Although the serum-dependent proliferation of HepG2 cells was inhibited by the MEK inhibitor PD98059 in a dose-dependent manner, 10 microM PD98059 reduced the HGF-induced strong activation of ERK to a weak activation; and as a result, the proliferation inhibited by HGF was completely restored. Above or below this specific concentration, the restoration was incomplete. Expression of constitutively activated Ha-Ras, which induces strong activation of ERK, led to the proliferation inhibition of HepG2 cells, as was observed in HGF-treated HepG2 cells. This inhibition was suppressed by the MEK inhibitor. Furthermore, HGF treatment and expression of constitutively activated Ha-Ras changed the hyperphosphorylated form of the retinoblastoma tumor suppressor gene product pRb to the hypophosphorylated form. This change was inhibited by the same concentration of MEK inhibitor needed to suppress the proliferation inhibition. These results suggest that ERK activity is required for both the stimulation and inhibition of proliferation of HepG2 cells; that the level of ERK activity determines the opposing proliferation responses; and that HGF-induced proliferation inhibition is caused by cell cycle arrest, which results from pRb being maintained in its active hypophosphorylated form via a high-intensity ERK signal in HepG2 cells.
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PMID:High intensity ERK signal mediates hepatocyte growth factor-induced proliferation inhibition of the human hepatocellular carcinoma cell line HepG2. 1153 45

Oxazepam is one of a number of benzodiazepines used therapeutically as a sedative-hypnotic and antianxiety agent. Toxicology and carcinogenesis studies were performed by administering oxazepam (greater than 99% pure) in feed to male and female Swiss-Webster and B6C3F1 mice for 14 weeks, 57 weeks (Swiss-Webster), or 2 years (B6C3F1). Neurobehavioral assessments were performed during the studies. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells, and peripheral blood samples were analyzed for frequency of micronucleated normochromatic erythrocytes. Supplemental studies were performed to compare the metabolism and toxicokinetics of oxazepam in the two mouse strains, to evaluate the effect on liver cell replication rates, to perform clinical pathology assessments, and to examine the mutation spectrum and frequency of activated H-ras oncogenes in liver neoplasms from the 2-year study with B6C3F1 mice. 14-WEEK STUDY IN SWISS-WEBSTER MICE: Groups of 10 male and 10 female Swiss-Webster mice received oxazepam in feed at concentrations of 0, 625, 1,250, 5,000, 10,000 ppm for 14 weeks. One 625 ppm male and one 10,000 female were killed moribund before the end of the study, and the condition of the female mouse was attributed to oxazepam exposure. Mean body weight gains of exposed groups were similar to those of the controls. Exposed mice displayed chemical-related sedation and lethargy during the first study week, but appeared normal thereafter. In the neurobehavioral studies, reductions in grip strength were evident in both male and female mice at week 2 and persisted in males through week 11. An antianxiety effect was detected in exposed mice in measures of motor activity, startle response, and reactions to thermal stimulus. At necropsy, absolute and relative liver weights were increased in an exposure-related manner and were approximately two-fold greater in 10,000 ppm mice than in controls. Centrilobular hepatocellular hypertrophy was present only in exposed mice, and the severity increased with dose. 14-WEEK STUDY IN B6C3F1 MICE: Groups of 10 male and 10 female B6C3F1 mice received oxazepam in feed at concentrations of 0, Groups of 10 male and 10 female Swiss-Webster mice 625, 1,250, 2,500, 5,000, or 10,000 ppm for 14 weeks. received oxazepam in feed at concentrations of 0, There were no deaths that were clearly related to 625,1,250, 2,500, 5,000, or 10,000 ppm for 14 weeks. oxazepam exposure. Mean body weight gains of One 625 ppm male and one 10,000 ppm female were exposed groups were similar to those of the controls. Exposed mice displayed chemical-related sedation and lethargy during only the first study week. In neurobehavioral studies, reductions in grip strength were evident in males at week 2 but were no longer observed at week 12. An antianxiety effect was noted in exposed mice in measures of motor activity, startle response, and reactions to a thermal stimulus (females). At necropsy, absolute and relative liver weights were increased in an exposure-related manner and were approximately two-fold greater in 10,000 ppm mice than in controls. Centrilobular hepatocellular hypertrophy was present only in exposed mice, and the severity increased with dose. CHRONIC STUDIES: Groups of 60 male and 60 female Swiss-Webster and B6C3F1 mice received oxazepam in feed at concentrations of 0, 2,500, or 5,000 ppm. Additional groups of 60 male and 60 female B6C3F1 mice received 125 ppm in feed to allow for study of a group with projected serum concentrations of oxazepam similar to those achieved in humans taking a therapeutic dose. Ten male and 10 female B6C3F1 mice per group were evaluated at 15 months. Average daily oxazepam consumption varied throughout the studies, and the overall daily average ranged from 10 to 29 mg/kg body weight for the 125 ppm groups, 234 to 512 mg/kg for the 2,500 ppm groups, and 444 to 1,085 mg/kg for the 5,000 ppm groups. Serum oxazepam concentrations determined at 57 weeks in Swiss-Webster mice and at the 15-month interim evaluation of B6C3F1 mice 1 mice were approximately 1 ug/mL in the 125 ppm groups, 4 to 7 μg/mL in the 2,500 ppm groups, and 7 to 10 μg/mL in the 5,000 ppm groups. Neurobehavioral assessments during the chronic studies of each strain of mice were confounded by the poor survival and deteriorating condition of mice with hepatic neoplasia. However, within the limitations of the studies, there were no notable changes in the types of behaviors observed compared to those observed in the 14-week studies, nor was there an enhancement in the degree to which they were exhibited. 57-Week Study in Swiss-Webster Mice: Survival, Body Weights, Feed and Compound Consumption, and Clinical Findings: At 57 weeks, survival of exposed mice was significantly lower than that of controls (males: O ppm, 45/60; 2,500 ppm, 19/60; 5,000 ppm, 10/60; females: 47/60, 28/59, 17/59), causing the study to be terminated. Mean body weights of exposed males were similar to controls until week 17; afterwards, mean body weights of exposed male groups were lower than those of controls. Final mean body weights of exposed males were 9% lower than that of the controls. The mean body weight of 2,500 ppm females was greater than that of the controls throughout the study. Females receiving 5,000 ppm had a mean body weight greater than that of the controls early in the study; after week 29, the mean body weight of this group was similar to that of the controls. Feed consumption by exposed males and females was slightly lower than that by the controls, and females in all groups, including controls, consumed slightly more feed than males throughout the study. Dietary levels of 2,500 and 5,000 ppm oxazepam resulted in average daily compound consumption levels of 270 and 570 mg/kg for males and 320 and 670 mg/kg for females. Hypoactivity and sedation were observed in exposed mice during the first week of the study. There were no other clinical findings associated with oxazepam exposure. Pathology Findings: Systemic amyloidosis was the principal cause of death in mice dying before the study was terminated. The lower survival of mice receiving oxazepam was attributed to an increase in the extent and severity of amyloid deposits in many organs, including the heart and kidney. Atrial thrombosis and pulmonary lesions consistent with chronic heart failure occurred at higher incidences and with greater severity in exposed mice. The incidence of hepatocellular adenomas (males: 1/60, 35/60, 50/60; females: 0/60, 22/59, 47/59) and carcinomas (males: 0/60, 5/60,19/60; females: 1/60, 1/59, 11/59) were increased in exposed mice. The incidences of eosinophilic foci were also increased in exposed mice (males: 0/60, 22/60, 22/60; females: 0/60, 20/59, 14/59), and there was evidence of increased centrilobular hepatocyte hypertrophy (males: 12/60, 46/60, 47/60; females: 3/60, 51/59, 53/59). 2-Year Study in B6C3F1 Mice: Survival, Body Weights, Feed and Compound Consumption, and Clinical Findings: Survival of mice receiving 2,500 and 5,000 ppm was significantly lower than that of controls (males: O ppm, 45/50; 125 ppm, 44/50; 2,500 ppm, 15/50; 5,000 ppm, 0/50; females: 39/50, 41/50, 2/50, 0/50). Mean body weight gains of exposed male and female mice were similar to controls until about week 15 when weight gains for mice exposed to 2,500 or 5,000 ppm slowed in relation to controls, resulting in weight gains approximately 30% to 40% lower than those of the controls throughout the remainder of the study. Mean body weight gain of male mice exposed to 125 ppm was similar to that of the controls, while that of female mice receiving 125 ppm was 10% to 15% lower than that of the controls after about week 45. Feed consumption by exposed males and females was similar to that by controls. Dietary levels of 125, 2,500, and 5,000 ppm resulted in average daily oxazepam consumption levels of 12, 310, and 690 mg/kg body weight for males and 15, 350, and 780 mg/kg for females. In the 5,000 ppm groups, lethargy and sedation were observed in a few mice during the first week of study. Pathology Findings: The early deaths of many of the B6C3F1 mice exposed to oxazepam were attributed to a marked increase in the incidences of hepatoblastoma (males: 0/49, 2/50, 21/50, 13/50; females: 0/50, 1/50, 8/50, 8/50), hepatocellular adenoma (males: 17/49,18/50, 34/50, 32/50; females: 25/50, 35/50, 35/50, 36/50), and hepatocellular carcinoma (males: 9/49, 5/50, 45/50, 50/50; females: 9/50, 5/50, 49/50, 44/50). Moderate hypertrophy of centrilobular hepatocytes occurred in mice receiving 2,500 and 5,000 ppm (males: 0/49, 2/50, 26/50, 43/50; females: 0/50, 2/50,11/50, 29/50). An increase in the incidence of follicular cell hyperplasia of the thyroid gland occurred in all exposed groups of mice (males: 4/49, 22/50, 49/50, 47/50; females: 16/50, 34/50, 49/50, 44/50), and thyroid gland follicular cell adenoma was increased in exposed females (0/50, 4/50, 5/50, 6/50). Testicular atrophy occurred in the 2,500 and 5,000 ppm groups (1/50, 0/50, 25/50, 38/50), and the incidence of epididymal Iymphocyte infiltration was increased in all exposed groups (2/50,14/50, 33/50, 21/50). The frequency of hepatocellular neoplasms with an activated H-ras oncogene in the B6C3F1 mice and the mutation spectrum of the H-ras gene were determined. The mutation spectrum of the H-ras genes in the relatively few neoplasms from exposed mice that did have an activated H-ras did not differ from the spectrum of mutations observed in neoplasms from controls, but the proportion of neoplasms with an activated H-ras gene decreased with increasing oxazepam dose. While 11 of 19 (58%) neoplasms from control mice had an activated H-ras gene, only 1 of 40 neoplasms from mice receiving 2,500 or 5,000 ppm oxazepam exhibited a similar molecular lesion. Thirteen of 37 (35%) neoplasms from mice in the 125 ppm group had an activated H-ras oncogene, suggesting that, although the incidence of all liver neoplasms was not statistically increased compared to controls, there was an increase in a similar subset of neoplasms (lacking an activated H-ras) that occurred with increased incidence at higher doses. SUPPLEMENTAL STUDIES: Because exposure to oxazepam caused increased incidences of liver neoplasms, supplemental short-term studies were performed. Oxazepam given in feed to male B6C3F1 mice at 25, 125, 2,500, or 5,000 ppm for up to 13 weeks was found to cause a dose-related increase in nuclear labeling index in studies measuring the incorporation of bromodeoxyuridine into replicating liver cells. This increase was statistically significant at all but the 25 ppm exposure level and was limited to mice evaluated at 15 days. Cell replication rates in most groups evaluated at 30 days and after were similar to control rates. There was minimal evidence suggestive of hepatocyte necrosis either by light microscopy or in clinical chemistry measures. There was, however, evidence of cholestasis, likely due to physical obstruction of bile canaliculi by swollen hepatocytes. The metabolic fate and toxicokinetics of oxazepam were evaluated in each strain of mice and were compared to published data from human studies. Both mice and humans form glucuronides of oxazepam and form 3- and 4-hydroxy and methoxy derivatives of the phenyl group. Oxidative metabolism of the phenyl group appears to be more prevalent in mice than is reported for humans. Elimination half-lives of parent compound do not differ between Swiss-Webster and B6C3F1 mice and are similar to values reported for humans. GENETIC TOXICOLOGY: Oxazepam was not mutagenic in any of several strains of Salmonella typhimurium, nor did it induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. These in vitro tests were performed with and without S9 metabolic activation. Results from an in vivo mouse peripheral blood micronucleus test performed on the B6C3F1 mice used in the 14-week study were also negative. CONCLUSIONS: Under the conditions of these feed studies, there was clear evidence of carcinogenic activity of oxazepam in male and female Swiss-Webster mice based on increased incidences of hepatocellular adenoma and carcinoma. There was clear evidence of carcinogenic activity of oxazepam in male and female B6C3F1 mice based on increased incidences of hepatoblastoma and hepatocellular adenoma and carcinoma. Increased incidences of hyperplasia of thyroid gland follicular cells in male and female B6C3F1 mice and of follicular cell adenomas in female B6C3F1 mice were also related to oxazepam exposure. Administration of oxazepam to Swiss-Webster mice resulted in centrilobular hepatocellular hypertrophy and increased incidences and severity of systemic amyloidosis. Administration of oxazepam to B6C3F1 mice also resulted in centrilobular hepatocellular hypertrophy. Synonyms: 7-Chloro-1,3-dihydro-3-hydroxy-5-phenyl-2 H - 1,4-benzodiazepin-2-one Trade Names: Tazepam, Wy-3498, Serax
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PMID:NTP Toxicology and Carcinogenesis Studies of Oxazepam (CAS No. 604-75-1) in Swiss-Webster and B6C3F1 Mice (Feed Studies). 1259 20

Mutational activation of beta-catenin and cyclin D1 over-expression are a frequent change in mouse hepatic tumors. Although activated beta-catenin may bind to T cell factor (TCF) family members and transcriptionally activate the cyclin D1 gene, either beta-catenin or cyclin D1 may be activated by various pathways independently of beta-catenin mutations. In this study, we investigated beta-catenin activation and mutations, cyclin D1 expression, H-ras mutations and phosphorylation of extracellular signal regulated protein kinases 1/2 (ERK1/2), Akt and glycogen synthetase kinase 3beta (GSK3 beta) in mouse hepatic carcinogenesis. Nuclear/cytoplasmic staining of beta-catenin, a sign of beta-catenin activation, was frequently observed in association with the high nuclear cyclin D1 labeling index in the hepatic tumors at the late stage of carcinogenesis. The beta-catenin activation was further suggested by the fact that all hepatocellular carcinoma (HCC) cell lines examined showed the nuclear beta-catenin/TCF4 complex together with cyclin D1 over-expression. However, the fact that only 31.8% (7/22) of the lesions with the nuclear/cytoplasmic beta-catenin staining showed beta-catenin mutations indicated that beta-catenin was activated not only by its own mutations but also by other reason(s). On the other hand, there was no correlation between the beta-catenin/cyclin D1 activation and the H-ras mutations or phosphorylation of Akt, GSK3 beta and ERK1/2, although GSK3 beta was frequently over-expressed in the tumors. These results indicate that, although beta-catenin and cyclin D1 activation are well correlated, the Akt/GSK3 beta and ras/ERK1/2 pathways may not play a major role in the beta-catenin/cyclin D1 activation.
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PMID:Cyclin D1 over-expression correlates with beta-catenin activation, but not with H-ras mutations, and phosphorylation of Akt, GSK3 beta and ERK1/2 in mouse hepatic carcinogenesis. 1266 2

Cancer is a genomic functional disease with features of oncogene activation and tumor suppressor inactivation. These genomic features have resulted in the limited effectiveness of conventional therapies and therefore forced considerable efforts to explore new types of anticancer agents. It has been clear that chemically synthesized or in vivo-expressed short interfering RNA (siRNA) can specifically and effectively direct homology-dependent post-transcriptional gene silencing. In the present study, we intended to investigate whether siRNA could suppress the proliferation of human cancer cells through interfering oncogene activities and recovering the functions of tumor-suppressor gene. Single siRNA or combinatorial siRNAs were successfully transfected into HeLa cells, lung adenocarcinoma cells, hepatoma cells, ovarian carcinoma cells, and melanoma cells with cationic lipid complexes. These siRNA molecules not only specifically knocked down their cognate targets such as bcl-2, cdk-2, mdm-2, pkc-alpha, tgf-beta1, H-ras, vegf, and GFP mRNAs, but also effectively suppressed the proliferation of cancer cells to different extents. These data suggest that (1) all these human cancer cells preserve RNAi machinery; (2) chemically synthesized and vector-driven siRNAs can be incorporated into intrinsic RNAi system for silencing target mRNA molecules; and (3) the combination of different siRNAs inhibits the growth and proliferation of cancer cells.
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PMID:siRNA agents inhibit oncogene expression and attenuate human tumor cell growth. 1456 90

We have established previously a mouse strain containing a mutant beta-catenin allele of which exon 3 was sandwiched by loxP sequences [Catnb(lox(ex3))]. In this mouse strain, a Wnt-activating beta-catenin mutation alone is insufficient for hepatocarcinogenesis, but additional mutations or epigenetic changes may be required. Here we report that hepatocellular carcinoma develops at the 100% incidence in mice with simultaneous mutations in the beta-catenin and H-ras genes that are introduced by adenovirus-mediated Cre expression. Although H-ras mutation alone rapidly causes large cell dysplasia in the hepatocytes, these cells show no autonomous growth within 1 week after infection of the Cre-adenovirus. However, simultaneous induction of an additional mutation in the beta-catenin gene causes a clonal expansion of such dysplastic cells, followed by nodular formation and development of hepatocellular carcinoma. These results indicate that beta-catenin mutations play a critical role in hepatocarcinogenesis in cooperation with another oncogene and that these mice provide a convenient model to investigate early steps of hepatocarcinogenesis.
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PMID:Hepatocarcinogenesis in mice with beta-catenin and Ha-ras gene mutations. 1472 7

We evaluated the effects of two putative non-genotoxic hepatic carcinogens, hexabromocyclododecane (HBCD) and 17-beta oestradiol (E(2)) on global and CpG promoter DNA methylation in both primary human hepatocytes and hepatocellular carcinoma (HepG2) cells. The mRNA gene expression levels of genes involved particularly in cell cycle were also evaluated and potential correlation with DNA methylation status examined. HBCD at 0.03 and 0.3 ng/mL did not produce statistically significant differences in global genomic methylation. However, E(2) (0.1 ng/mL) significantly lowered global DNA methylation levels in HepG2 cells by approximately 65% (P<0.01). In primary hepatocytes, the promoter regions of N-cym and ERalpha were methylated in both control and treated groups, signifying lack of promoter demethylation by both HBCD and E(2). Furthermore, CpG promoter methylation of RB1 was observed in HepG2 cells but this was unaffected by treatments. The remaining genes (p16, C-myc, H-ras, THRalpha, histone H3, TBK1 and TNFRalpha) were unmethylated in their CpG promoter regions in both test systems. Quantitative RT-PCR showed that HBCD at 0.03 ng/mL up-regulated the expression of N-cym whereas E(2) up-regulated the expression of ERalpha and THRalpha genes in primary hepatocytes. In HepG2 cells, the mRNA gene expression levels of p16, RB1 and N-cym were significantly down regulated by HBCD (0.03 ng/mL) and E(2) (0.1 ng/mL) while HBCD at 0.3 ng/mL, significantly down regulated the expression levels of N-cym, ERalpha and ERbeta genes. Thus, while both HBCD and E(2) may alter the expression of certain genes involved in proliferation, the mechanisms appear unrelated to DNA methylation.
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PMID:Changes in gene expression and assessment of DNA methylation in primary human hepatocytes and HepG2 cells exposed to the environmental contaminants-Hexabromocyclododecane and 17-beta oestradiol. 1902 19

Recently, we found epigenetic silencing of the Ras effector genes NORE1B and/or RASSF1A in 97% of the hepatocellular carcinoma (HCC) investigated. This is strong evidence that the two genes are of major significance in hepatocarcinogenesis. Although RASSF1A serves as a tumor suppressor gene, the functions of NORE1B are largely unknown. Here, we studied the role of NORE1B for growth and transformation of cells. To understand the molecular mechanisms of action of the gene, we used the wild-type form and deletion mutants without the NH(2) terminus and CENTRAL domain, the Ras association (RA) domain, or the COOH-terminal SARAH-domain. Intact RA and SARAH-domains were found to be necessary for NORE1B (a) to increase the G(0)-G(1) fraction in hepatoma cells, (b) to suppress c-Myc/Ha-Ras-induced cell transformation, and (c) to interact closely with RASSF1A, as determined with fluorescence resonance energy transfer. In further studies, cell cycle delay by NORE1B was equally effective in hepatocyte cell lines with wild-type or mutant Ras suggesting that NORE1B does not interact with either Ras. In conclusion, NORE1B suppresses replication and transformation of cells as effectively as RASSF1A and thus is a putative tumor suppressor gene. NORE1B interacts physically with RASSF1A and functional loss of one of the interacting partners may lead to uncontrolled growth and transformation of hepatocytes. This may explain the frequent epigenetic silencing of NORE1B and/or RASSF1A in HCC.
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PMID:NORE1B is a putative tumor suppressor in hepatocarcinogenesis and may act via RASSF1A. 1911 8

This study was designed to assess the impact of several molecular markers and clinicopathological characteristics on postoperative survival of patients with hepatocellular carcinoma (HCC). Postoperative clinical data of 64 patients with HCC were retrospectively analyzed. K-ras, PIK3CA, and BRAF gene mutations in surgically resected specimens of the 64 patients with HCC were detected by pyrosequencing. H-ras and XB130 protein expression was examined by immunohistochemistry. A Cox proportional hazards regression model was used for univariate and multivariate survival analyses of the clinical and pathological parameters. The mutation rates of K-ras, PIK3CA, and BRAF genes in HCC were found to be 4.69%, 1.56%, and 0%, respectively. Positive expression rate of XB130 and H-ras in HCC was 75.0% and 93.8%, respectively. Univariate analysis revealed that clinicopathological factors impacting postoperative prognosis of patients with HCC include clinical stage, tumor diameter, and postoperative transcatheter arterial embolization therapy for HCC. Meanwhile, multivariate analysis showed that clinical stage (relative risk [RR]: 6.420, P = 0.013) and tumor diameter (RR: 1.498, P = 0.014) were independent factors impacting postoperative survival of patients with HCC. These findings indicate that the clinical stage and tumor diameter are independent risk factors impacting postoperative survival of patients with HCC. Gene mutations of K-ras and PIK3CA and protein expression of XB130 and H-ras are not associated with the postoperative prognosis of patients with HCC.
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PMID:Multivariate analysis of several molecular markers and clinicopathological features in postoperative prognosis of hepatocellular carcinoma. 2219 Feb 83

The aim of this study was to investigate the correlation between H-ras mutation and primary hepatocellular carcinoma (HCC) and to describe the role of H-ras mutation in carcinogenesis. Clinical samples of 69 patients were collected and the expression levels of H-ras in HCC and the surrounding normal tissues were examined using HotStarTaq PCR. H-ras mutation was further analyzed using the PCR direct sequencing method. The results showed that H-ras mutation was present in 49 samples (49/69, 71.01%), of which 19 had codon 40 mutated from CTA to CTG and 30 had codon 61 mutated from GGC to AGC. By contrast, only 2 mutations were found in the normal tumor-adjacent tissues. The H-ras mutation rate in the high-risk of metastatic recurrence group was markedly higher than that in the low-risk group (P<0.01). The H-ras mutation rate in patients with metastatic recurrence during postoperative follow-up was also significantly higher than that in patients without metastatic recurrence (P<0.01). Based on the above results, the H-ras mutation frequency in cancer tissues is markedly higher compared with that in normal tissues. H-ras mutation may play an important role in the genesis and development of HCC and may serve as a reliable marker for individual comprehensive therapy in HCC.
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PMID:Study of the correlation between H-ras mutation and primary hepatocellular carcinoma. 2320


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