• Asian Pacific Journal of Cancer Prevention
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• 제15권1호
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• pp.123-127
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• 2014

A recent study summarized several published genome-wide association studies (GWASs) of cancer and reported two pleiotropic loci at 6p21.1 and 7p15.3 contributing to multiple cancers including lung cancer, noncardia gastric cancer (NCGC), and esophageal squamous-cell carcinoma (ESCC) in Han Chinese. However, it is not known whether such genetic variants have similar effects on the risk of gynecologic cancers, such as ovarian cancer. Hence, we explored associations between genetic variants in 6p21.1 and 7p15.3 and ovarian cancer risk in Han Chinese women. We performed an independent case-control study by genotyping the two loci (rs2494938 A > G at 6p21.1 and rs2285947 A > G at 7p15.3) in a total of 377 ovarian cancer cases and 1,034 cancer-free controls using TaqMan allelic discrimination assay. We found that rs2285947 at 7p15.3 was significantly associated with risk of ovarian cancer with per allele odds ratio (OR) of 1.33 [95% confidence interval (CI): 1.08-1.64, P=0.008]. However, no significant association was observed between rs2494938 and ovarian cancer risk. Our results showed that rs2285947 at 7p15.3 may also contribute to the development of ovarian cancer in Han Chinese women, further suggesting pleiotropy of 7p15.3 in multiple cancers.

• Asian Pacific Journal of Cancer Prevention
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• 제15권1호
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• pp.495-499
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• 2014

Estrogens are considered the major breast cancer risk factor, and the carcinogenic potential of estrogens might be attributed to DNA modification caused by derivatives formed during metabolism. $17{\beta}$-estradiol ($E_2$), the main steroidal estrogen present in women, is metabolized via two major pathways: formation of 2-hydroxyestradiol (2-OH $E_2$) and 4-hydroxyestradiol ($4-OH\;E_2$) through the action of cytochrome P450 (CYP) 1A1 and 1B1, respectively. Previous reports suggested that $2-OH\;E_2$ has putative protective effects, while $4-OH\;E_2$ is genotoxic and has potent carcinogenic activity. Thus, the ratio of $2-OH\;E_2/4-OH\;E_2$ is a critical determinant of the toxicity of $E_2$ in mammary cells. In the present study, we investigated the effects of berberine on the expression profile of the estrogen metabolizing enzymes CYP1A1 and CYP1B1 in breast cancer MCF-7 cells. Berberine treatment produced significant induction of both forms at the level of mRNA expression, but with increased doses produced 16~ to 52~fold greater induction of CYP1A1 mRNA over CYP1B1 mRNA. Furthermore, berberine dramatically increased CYP1A1 protein levels but did not influence CYP1B1 protein levels in MCF-7 cells. In conclusion, we present the first report to show that berberine may provide protection against breast cancer by altering the ratio of CYP1A1/CYP1B1, could redirect $E_2$ metabolism in a more protective pathway in breast cancer MCF-7 cells.

• Asian Pacific Journal of Cancer Prevention
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• 제15권3호
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• pp.1441-1446
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• 2014

Squamous cell/adenosquamous carcinoma (SC/ASC) of the gallbladder are rare tumors and there are few clinical reports in the literature. Herein we report our clinical experience with 46 patients with SC/ASC and 80 with adenocarcinoma (AC). Expression of EphB1 and Ephrin-B in each tumor was determined using immunohistochemical methods for determination of correlations with prognosis. There was no difference in EphB1 and Ephrin-B expression between SC/ASC and AC tumors (P>0.05), but greater expression in those less than 3 cm in diameter, stage I or II (TNM stage), with no lymph node metastases, with no local invasion and treated with radical resection was apparent. Expression of EphB1 (P<0.05) and Ephrin-B (P<0.01) was higher in well differentiated than in poorly differentiated AC tumors. Kaplan-Meier survival analysis indicated that degree of differentiation, tumor diameter, lymph node metastases, local invasion, surgical approach and expression rate of EphB1 and Ephrin-B were closely related to the survival of SC/ASC (P<0.05) and AC patients (P<0.01). Patients with tumors that positive expressed EphB1 and Ephrin-B, whether it is SC/ASC ($P_{SC/ASC}$ =0.000) or AC ($P_{AC}$ =0.000 or $P_{AC}$ =0.002) had longer survival than those negative expression. Cox multivariate analysis indicated a negative correlation between expression of EphB1 or Ephrin-B and overall survival. Hence, EphB1 and Ephrin-B could be regarded as independent good prognostic factorsand important biological markers for SC/ASC and AC of gallbladder.

• Asian Pacific Journal of Cancer Prevention
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• 제15권16호
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• pp.6737-6743
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• 2014

It is reported that sinomenine (SIN) and 5-fluorouracil (5-FU) both are effective for colon cancer, but their cooperative suppressive effects and toxicity remain to be clarified in detail. This study aimed to determine suppressive effects and toxicity of sinomenine (SIN) plus 5-fluorouracil (5-FU) on LoVo colon carcinoma cells in vitro and in vivo. CCK-8, Hoechst 33258 staining and an annexin V-FITC/PI apoptosis kit were used to detect suppressive effects. Western blotting was applied to investigate the essential mechanism underlying SIN and 5-FU-induced apoptosis. SIN or 5-FU or both were injected into nude mice, and then suppressive effects and side effects were observed. SIN plus 5-FU apparently inhibited the proliferation of LoVo cells and induced apoptosis. Moreover the united effects were stronger than individually (p<0.05). The results of annexin V-FITC/PI staining and Hoechst 33258 staining showed that the percentage of apoptotic cells induced by SIN and 5-FU combined or alone was significantly higher than the control group (p<0.05). Expression of Bax and Bcl-2 was up-regulated and down-regulated respectively. SIN or 5-FU significantly inhibited effects on the volume of tumour xenografts and their combined suppressive effects were stronger (p<0.05). No obvious side effects were observed. It was apparent that the united effects of SIN and 5-FU on the growth of colorectal carcinoma LoVo cells in vitro and in vivo were superior to those using them individually, and it did not markedly increase the side effects of chemotherapy.

• Asian Pacific Journal of Cancer Prevention
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• 제15권6호
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• pp.2641-2646
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• 2014

Background: To evaluate efficacy and side effects of glycididazole sodium (CMNa) combined with chemotherapy (cisplatin plus 5-FU/folic acid, PLF) and radiotherapy in treating patients with locally advanced nasopharyngeal carcinoma. Materials and Methods: Patients with III~IV stage nasopharyngeal carcinoma (NPC),were randomly divided into treatment group (46 patients) and control group (45 patients). Both groups received radiotherapy concomitant with PLF chemotherapy. The treatment group at the same time cwas given CMNa ($800mg/m^2$ before radiotherapy), by l h intravenous drip, three times a week. Results: When the dose of radiation was over 60 Gy, complete response rates of nasopharyngeal tumor and lymph node metastases in treatment group were significantly higher than in the control group (93.5% vs 77.8%; 89.1% vs 93.5%, p<0.05). Three months after radiotherapy, complete response rate of nasopharynx cancer and lymph node metastases in treatment group was both 97.8%, again higher than in the control group (84.4% and 82.2%) (p<0.05). In the treatment group, 1, 3, 5 year disease-free survival rates were 95.7%, 86.7% and 54.5%; and in control group, the corresponding disease-free survival rates were 93.3%, 66.2% and 38.6%, respectively, the difference being statistically significant (log-rank =5.887, p=0.015). One, 3, 5 year overall survival rates in two groups of patients were 97.8%, 93.5%, 70.4% and 95.5%, 88.07%, 48.4%, respectively, again with a statistically significant difference (log-rank=6.470, p=0.011). Acute toxicity and long-term radiotherapy related toxicity in the two groups did not differ (p>0.05). Conclusions: Glycididazole sodium could improve curative effects without increasing adverse reactions when treating paitents with locally advanced nasopharyngeal carcinoma.

• Asian Pacific Journal of Cancer Prevention
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• 제15권3호
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• pp.1321-1326
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• 2014

Background/Aim: Toll-like receptor 4 (TLR4) and B7-H1, both normally expressed restricted to immune cells, are found to be aberrantly expressed in a majority of human tumors and may play important roles in regulation of tumor immunity. It has been shown that urothelial bladder cancer (UBC) patients can manifest tumoral immune escape which may be a potential critical factor in tumor pathogenesis and progression. However, so far, the mechanisms of UBC-related immune escape have not been clarified. The aim of this study was to investigate the effect of TLR4 and B7-H1 on immune escape of UBC. Methods: Bladder cancer T24 cells were pre-incubated with LPS and co-cultured with tumor specific CTLs. CTL cytotoxicity and apoptosis rates were measured by MTT assay and flow cytometry, respectively. The effects of an ERK inhibitor on B7-H1 expression and CTL cytotoxicity against T24 cells were also evaluated. In addition, TLR4, B7-H1 and PD-1 protein expression was analyzed by immunohistochemistry in 60 UBC specimens and 10 normal urothelia. Results: TLR4 activation protected T24 cells from CTL killing via B7-H1 overexpression. However PD98059, an inhibitor of ERK, enhanced CTL killing of T24 cells by reducing B7-H1 expression. TLR4 expression was generally decreased in UBC specimens, while B7-H1 and PD-1 were greatly overexpressed. Moreover, expression of both B7-H1 and PD-1 was significantly associated with UICC stage and WHO grade classification. Conclusions: TLR4 and B7-H1 may contribute to immune escape of UBC. Targeting B7-H1 or the ERK pathway may offer new immunotherapy strategies for bladder cancer.

• Asian Pacific Journal of Cancer Prevention
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• 제15권3호
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• pp.1313-1320
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• 2014

Introduction: Although most prostate cancers initially respond to castration with luteinizing hormonereleasing analogues or bilateral orchiectomy, progression eventually occurs. Based on the exciting results of several randomized controlled trials (RCTs), it seems that patients with metastatic castration-resistant prostate cancer (mCRPC) might benefit more from treatment withabiraterone. Therefore we conducted a systematic review to evaluate the efficacy and toxicity of abiraterone in the treatment of mCRPC. Methods: Literature was searched from Embase, PubMed, Web of Science, and Cochrane Library up to July, 2013. Quality of the study was evaluated according to the Cochrane's risk of bias of randomized controlled trial (RCT) tool, then the Grading of Recommendations Assessment, Development and Evaluation (GRADE) System was used to rate the level of evidence. Stata 12.0 was used for statistical analysis. Summary data from RCTs comparing abiraterone plus prednisone versus placebo plus prednisone for mCRPC were meta-analyzed. Pooled hazard ratios (HRs) for overall survival (OS), radiographic progression-free survival (RPFS) and time to PSA progression (TTPP); Pooled risk ratios (RR) for PSA response rate, objective response rate and adverse event were calculated. Results: Ten trials were included in the systematic review; Data of 2,283 patients (1,343 abiraterone; 940 placebo) from two phase 3 trials: COU-AA-301 and COU-AA-302 were meta-analyzed. Compared with placebo, abiraterone significantly prolonged OS (HR, 0.74; 95% confidence interval [CI], 0.66 to 0.84), RPFS (HR, 0.59; 95% CI, 0.48 to 0.74) and time to PSA progression (HR, 0.55; 95% CI, 0.43 to 0.70); it also significantly increased PSA response rate (RR, 3.63; 95% CI, 1.72 to 7.65) and objective response rate (RR, 3.05; 95% CI, 1.51 to 6.15). This meta-analysis suggested that the adverse events caused by abiraterone are acceptable and can be controlled. Conclutios: Abiraterone significantly prolonged OS, RPFS and time to progression patients with mCRPC, regardless of prior chemotherapy or whether chemotherapy-na$\ddot{i}$ve, and no unexpected toxicity was evident. Abiraterone can serve as a new standard therapy for mCRPC.

• Asian Pacific Journal of Cancer Prevention
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• 제15권6호
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• pp.2591-2596
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• 2014

Purpose: To evaluate the prognostic value of the expression of excision repair cross-complementation group l (ERCC1), MutS protein homolog 2 (MSH2) and poly ADP-ribose polymerase 1 (PARP1) in non-small-cell lung cancer patients receiving platinum-based postoperative adjuvant chemotherapy. Methods: Immunohistochemistry was applied to detect the expression of ERCC1, MSH2 and PARP1 in 111 cases of non-small cell lung cancer paraffin embedded surgical specimens. Through og-rank survival analysis, we evaluated the prognostic value of the ERCC1, MSH2, PARP1 and the related clinicopathological factors. COX regression analysis was used to determine whether ERCC1, MSH2 and PARP1 were independent prognostic factors. Results: In the enrolled 111 non-small cell lung cancer patients, the positive expression rate of ERCC1, MSH2 and RARP1 was 33.3%, 36.9% and 55.9%, respectively. ERCC1 (P<0.001) and PARP1 (P=0.033) were found to be correlated with the survival time while there was no correlation for MSH2 (P=0.298). Patients with both ERCC1 and PARP1 negative cancer had significantly longer survival time than those with ERCC1 (P=0.042) or PARP1 (P=0.027) positive alone. Similalry, the survival time of patients with both ERCC1 and PARP1 positive cancer was shorter than those with ERCC1 (P=0.048) or PARP1 (P=0.01) positive alone. Conclusion: Patients with ERCC1 or PARP1 negative non-small cell lung cancer appear to benefit from platinum-based postoperative adjuvant chemotherapy.

• Asian Pacific Journal of Cancer Prevention
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• 제15권6호
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• pp.2753-2758
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• 2014

Background: GC-binding factor 2 (GCF2) is a transcriptional regulator that represses transcriptional activity of the epidermal growth factor receptor (EGFR) by binding to a specific GC-rich sequence in the EGFR gene promoter. In addition to this function, GCF2 has also been identified as a tumor-associated antigen and regarded as a potentially valuable serum biomarker for early human hepatocellular carcinoma (HCC) diagnosis. GCF2 is high expressed in most HCC tissues and cell lines including HepG2. This study focused on the influence of GCF2 on cell proliferation and apoptosis in HepG2 cells. Materials and Methods: GCF2 expression at both mRNA and protein levels in HepG2 cells was detected with reverse transcription (RT) PCR and Western blotting, respectively. RNA interference (RNAi) technology was used to knock down GCF2 mRNA and protein expression. Afterwards, cell viability was analyzed with a Cell Counting Kit-8 (CCK-8), and cell apoptosis and caspase 3 activity by flow cytometry and with a Caspase 3 Activity Kit, respectively. Results: Specific down-regulation of GCF2 expression caused cell growth inhibition, and increased apoptosis and caspase 3 activity in HepG2 cells. Conclusions: These primary results suggest that GCF2 may influence cell proliferation and apoptosis in HepG2 cells, and also provides a molecular basis for further investigation into the possible mechanism at proliferation and apoptosis in HCC.

• Asian Pacific Journal of Cancer Prevention
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• 제15권12호
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• pp.5001-5007
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• 2014

The acetyltransferase inhibitor garcinol, a polyisoprenylated benzophenone, is extracted from the rind of the fruit of Garcinia indica, a plant found extensively in tropical regions. Anti-cancer activity has been suggested but there is no report on its action via inhibiting acetylation against cell proliferation, cell cycle progression, and apoptosis-inhibtion induced by estradiol ($E_2$) in human breast cancer MCF-7 cells. The main purposes of this study were to investigate the effects of the acetyltransferase inhibitor garcinol on cell proliferation, cell cycle progression and apoptosis inhibition in human breast cancer MCF-7 cells treated with estrogen, and to explore the significance of changes in acetylation levels in this process. We used a variety of techniques such as CCK-8 analysis of cell proliferation, FCM analysis of cell cycling and apoptosis, immunofluorescence analysis of NF-${\kappa}B$/p65 localization, and RT-PCR and Western blotting analysis of ac-H3, ac-H4, ac-p65, cyclin D1, Bcl-2 and Bcl-xl. We found that on treatment with garcinol in MCF-7 cells, $E_2$-induced proliferation was inhibited, cell cycle progression was arrested at G0/G1 phase, and the cell apoptosis rate was increased. Expression of ac-H3, ac-H4 and NF-${\kappa}B$/ac-p65 proteins in $E_2$-treated MCF-7 cells was increased, this being inhibited by garcinol but not ac-H4.The nuclear translocation of NF-${\kappa}B$/p65 in $E_2$-treated MCF-7 cells was also inhibited, along with cyclin D1, Bcl-2 and Bcl-xl in mRNA and protein expression levels. These results suggest that the effect of $E_2$ on promoting proliferation and inhibiting apoptosis is linked to hyperacetylation levels of histones and nonhistone NF-${\kappa}B$/p65 in MCF-7 cells. The acetyltransferase inhibitor garcinol plays an inhibitive role in MCF-7 cell proliferation promoted by $E_2$. Mechanisms are probably associated with decreasing ac-p65 protein expression level in the NF-${\kappa}B$ pathway, thus down-regulating the expression of cyclin D1, Bcl-2 and Bcl-xl.