Quantitative analysis of heparanase messenger RNA expression in hepatocellular carcinoma

Ikeguchi, Masahide; Ueta, Tsuyoshi; Yamane, Yoshio; Hirooka, Yasuaki; Kaibara, Nobuaki

doi:10.1002/jso.10163

Cited by 17 publications

(13 citation statements)

References 11 publications

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“…Patients in the study of ElAssal et al [14] were mainly infected with HCV, but most HCCs in China were related to HBV infection and posthepatitic cirrhosis, few were infected with HCV. In addition, our conclusions are different from those of Ikeguchi et al [15] , in which relative heparanase mRNA expression level in HCC was significantly lower than that in noncancerous liver tissues, and tumor heparanase expression did not correlate with tumor differentiation, tumor stage, or patient prognosis. Both the discrepancy of hepatitis virus and experimental methods could contribute to the different results.…”

Section: Discussioncontrasting

confidence: 99%

“…However, in their studies, over half of HCC patients (52.7%, 29/55) were accompanied with HCV infection, and few were associated with hepatitis B virus (HBV). Ikeguchi et al [15] found that relative heparanase mRNA expression level in HCC was significantly lower than that in noncancerous liver tissues (P<0.001), and that tumor heparanase expression did not correlate to tumor differentiation, tumor stage, or patient prognosis. They concluded that enhanced heparanase mRNA expression might not be a good biological marker for HCC.…”

Section: Introductionmentioning

confidence: 99%

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Heparanase mRNA expression and point mutation in hepatocellular carcinoma

Chen

Liu²,

Rui³

et al. 2004

WJG

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AIM:To explore the expression of heparanase mRNA and point mutation in hepatocellular carcinoma (HCC). METHODS:Reverse transcription polymerase chain reaction was used to measure the expression of heparanase mRNA in the primary tumor tissues and surrounding liver tissues of 33 HCC patients. T-A cloning and sequencing were used to detect whether there was any mutation in the amplified PCR products. RESULTS:The expression of heparanase mRNA was positive in 16 primary tumor tissues of HCC, and the positive rate was 48.5%, which was significantly higher than that in the surrounding liver parenchyma (P<0.01). The positive rate for heparanase gene in high-tendency to metastatic recurrence group (71.4%, 10/14) was obviously higher than that in low-tendency to metastatic recurrence group (31.6%, 6/19) (P = 0.023). The positive rate for heparanase gene in patients with metastatic recurrence during postoperative follow-up (78.6%, 11/14) was also significantly higher than that in those without metastatic recurrence (21.4%, 3/14) (P = 0.003). Sequence analysis of the HPA PCR products was made in 7 patients, and 2-point mutations were found in 4 patients, one of which was sense mutation, neither base insertion nor deletion was detected. The mutation rate was 57.1% (4/7). CONCLUSION:The expression rate of heparanase mRNA increases in HCC, and HPA mRNA may be one of the reliable markers for the metastatic activity gained by the liver tumor cells and could be used clinically in predicting metastatic recurrence of HCC. Point mutation may be one of the causes for enhanced heparanase mRNA expression.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Heparanase mRNA expression and point mutation in hepatocellular carcinoma

Chen

Liu²,

Rui³

et al. 2004

WJG

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“…Tissues-Many previous studies showed that elevated survivin expression was observed in human cancers of various origins (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Our data indicate that the intermediates in the cholesterol synthesis pathway, particularly FPP and GGPP, regulate survivin expression.…”

Section: Survivin Mrna Expression Correlates With Hmg-coa Reductase Mmentioning

confidence: 53%

“…Elevated survivin expression was observed in human cancers of various origins such as the breast (13), esophagus (14), stomach (15,16), colon (17,18), pancreas (19), liver (20), uterus (21), and ovaries (22) as well as in leukemias (23). Since survivin overexpression desensitized cancer cells to several anticancer agents (24) and to irradiation (25), which induce apoptosis, it acts as a resistance factor against these cancer treatment modalities.…”

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confidence: 99%

Survivin Down-regulation Plays a Crucial Role in 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitor-induced Apoptosis in Cancer

Kaneko¹,

Tsuji²,

Asanuma

et al. 2007

Journal of Biological Chemistry

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3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HRIs) are widely used to reduce serum cholesterol in patients with hypercholesterolemia. Previous studies have shown that HRIs can induce apoptosis in colon cancer cells. In this study, we investigated the mechanisms underlying the apoptosis-inducing effect of HRIs in greater detail. The HRI lovastatin induced apoptosis in the human colon cancer cell line SW480 by blocking the cholesterol synthesis pathway. Immunoblot analysis of antiapoptotic molecules, including survivin, XIAP, cIAP-1, cIAP-2, Bcl-2, and Bcl-X L , revealed that only survivin expression was decreased by lovastatin. Survivin downregulation by RNA interference induced apoptosis, and survivin overexpression rendered the cells resistant to lovastatin-induced growth inhibition. These results indicate that survivin downregulation contributes substantially to the proapoptotic properties of lovastatin. Farnesyl pyrophosphate and geranylgeranyl pyrophosphate, two downstream intermediates in the cholesterol synthesis pathway, simultaneously reversed survivin down-regulation and the blocking of Ras isoprenylation by lovastatin. Ras isoprenylation is important for the activation of Ras-mediated signaling, including the activation of the phosphatidylinositol 3-kinase (PI3-kinase)/Akt pathway. The PI3-kinase inhibitor down-regulated survivin in SW480 cells. In addition, lovastatin blocked Ras activation and Akt phosphorylation. We conclude that survivin down-regulation is crucial in lovastatin-induced apoptosis in cancer cells and that lovastatin decreases survivin expression by inhibiting Ras-mediated PI3-kinase activation via the blocking of Ras isoprenylation.3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) 3 reductase inhibitors (HRIs) are widely used to reduce serum cholesterol and are well tolerated by patients with hypercholesterolemia (1). HRIs prevent the formation of mevalonate from HMG-CoA by inhibiting the enzyme HMG-CoA reductase, thereby inhibiting cholesterol synthesis (2). In large clinical trials designed to study the changes in coronary events in coronary heart disease patients receiving HRIs, the number of newly diagnosed colon cancer cases showed a reduction of between 43% (3) and 19% (4) during a 5-year follow-up period. It has been reported that HRIs could induce apoptosis in colon cancer cells (5-7). Farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), two downstream intermediates in the cholesterol synthesis pathway, belong to a class of compounds named isoprenoids. They are bound to several cellular proteins, including small GTPases such as Ras, Rho, and Rac, by a posttranslational modification known as isoprenylation. This process involves the addition of a 15-carbon farnesyl chain in FPP (farnesylation) or a 20-carbon geranylgeranyl chain in GGPP (geranylgeranylation) to a cysteine sulfhydryl group near the carboxyl terminus. Isoprenylation of these proteins is crucial for membrane attachment (8, 9) and the subsequent acquisition of biological activity (10)...

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“…The majority of papers report on the elevation of HPSE mRNA and/or protein in HCC relative to both adjacent non-tumorous and normal liver tissue, and most investigations have found significant positive correlation between tumoral HPSE levels, HCC progression, and adverse prognosis. In some studies, however, the levels of HPSE mRNA were found to be decreased in HCC when compared to adjacent noncancerous tissue (Ikeguchi et al, 2002(Ikeguchi et al, , 2003, and mean HPSE mRNA expression was shown to be elevated in HCC relative to the healthy liver but lower than in fibrogenic diseases (Tátrai et al, 2010). In explanation of a supposed tumor-inhibitory effect it has been proposed that, as opposed to the stimulatory effect of moderate HPSE activity, excessive HS fragmentation by HPSE may be detrimental to FGF-2 signaling and may therefore lead to increased apoptosis rates (Ikeguchi et al, 2003;Dong & Wu, 2010).…”

Section: Enzymes Involved In Hs Synthesis and Modificationmentioning

confidence: 99%