Impact of Aurora Kinase A Polymorphism and Epithelial Growth Factor Receptor Mutations on the Clinicopathological Characteristics of Lung Adenocarcinoma.

Lung adenocarcinoma (LADC) is the most common subtype of lung cancer worldwide and the epidermal growth factor receptor (EGFR) has a great influence on its clinical course, mainly due to the influence of different phenotypes. The Aurora kinase A (AURKA) would influence the progression of several solid malignancies. However, whether the interaction between EGFR phenotypes and AURKA would influence the clinical characteristics of LADC remains unknown. Herein, this study aimed to explore the effects of single-nucleotide polymorphisms (SNPs) of AURKA and EGFR phenotypes on the clinicopathological characteristics of LADC. Four loci of AURKA SNPs (rs1047972, rs2273535, rs6024836, and rs2064863) were genotyped using TaqMan allelic discrimination in 105 wild-type EGFR individuals and 167 LADC patients with EGFR mutations. After the statistical analysis, patients with LADC who had CT heterozygotes of AURKA rs1047972 had a lower risk of EGFR mutations than patients with wild-type homozygotes. Moreover, female and nonsmoking patients who carried the CT genotype of AURKA rs1047972 had a lower risk of EGFR mutation (p = 0.008 and p = 0.004, respectively). Moreover, in patients with EGFR mutations, AURKA SNP rs6024836 G allele (AG + GG) carriers had a lower risk of developing advanced-stage LADC (stage III or IV; odds ratio = 0.423, 95% confidence interval: 0.203-0.879, p = 0.019) than patients with AA homozygotes. Our results suggested that AURKA rs1047972 variants are significantly associated with EGFR mutations among patients with LADC, particularly in female and nonsmoking patients. AURKA variants may contribute to the pathological development of LADC.

The Impact of HMGB1 Polymorphisms on Prostate Cancer Progression and Clinicopathological Characteristics.

Prostate cancer is one of the major cancers of the genitourinary tract. High-mobility group box 1 (HMGB1) was suggested as a promising therapeutic target for prostate cancer. In this study, we aim to elucidate the associations of HMGB1 single nucleotide polymorphisms (SNPs) with prostate cancer susceptibility and clinicopathological characteristics. The HMGB1 SNPs rs1412125, rs2249825, rs1045411, and rs1360485 in 579 prostate cancer patients and 579 cancer-free controls were analyzed with real-time polymerase chain reactions (real-time PCR). All of the data were evaluated with SAS statistical software. Our results showed that the HMGB1 rs1045411 T allele genotype was significantly associated with advanced pathologic T stage (odds ratio (OR) = 1.433, 95% confidence interval (CI) = 1.021‒2.012; p = 0.037) and pathologic N1 stage (OR = 2.091, 95% CI = 1.160‒3.767; p = 0.012), and the rs1360485 polymorphic CT + TT genotype was associated with pathologic Gleason grade group (4 + 5) (OR = 1.583, 95% CI = 1.017‒2.462; p = 0.041), pathologic T stage (3 + 4) (OR = 1.482, 95% CI = 1.061‒2.070; p = 0.021), and pathologic N1 stage (OR = 2.131, 95% CI = 1.178‒3.852; p = 0.011) compared with their wild-type carriers. In conclusion, our results revealed that the HMGB1 SNPs were associated with the clinical status of prostate cancer. The HMGB1 SNPs may have the potential to predict prostate cancer disease progression.

Association of lncRNA CCAT2 and CASC8 Gene Polymorphisms with Hepatocellular Carcinoma.

The worldwide incidence of hepatocellular carcinoma (HCC), the major histological type of primary liver cancer, is heterogeneous due to the variable prevalence of etiological factors, indicating a correlation of HCC risk with genetic variations among individuals. Among long non-coding RNAs (lncRNAs) located in the chromosome 8q24 loci and involved in the carcinogenesis are colon cancer associated transcript 2 (CCAT2) and cancer susceptibility candidate 8 (CASC8). In this study, the association of CCAT2 and CASC8 gene polymorphisms with the occurrence of HCC was explored between 397 HCC patients and 1195 controls. We found that carriers of rs6983267 GG in CCAT2 were more susceptible to HCC, with the odds ratio (OR) and adjusted odds ratio (AOR) being 1.532 (95% CI, 1.103-2.129; p = 0.011) and 1.627 (95% CI, 1.120-2.265; p = 0.033), respectively. Moreover, for patients stratified by age (under 65), gender (male only), or status of drinking (habitual drinkers), a protective effect of CASC8 rs3843549 on presenting high Child-Pugh scores, metastatic vascular invasion, or large-size tumors was observed in a dominant model. Collectively, our data reveal association of CCAT2 and CASC8 gene polymorphisms with the occurrence and progression of HCC.

Correlation of E-cadherin gene polymorphisms and epidermal growth factor receptor mutation in lung adenocarcinoma.

Epithelial-mesenchymal transition (EMT) was recently discovered related to the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in NSCLC patients and cell lines. In this study, we aimed to explore the association among the E-cadherin gene (CDH1) genetic variants, TK-domain mutations of EGFR, and clinicopathologic characteristics in patients with lung adenocarcinoma. A total of 280 patients with lung adenocarcinoma were recruited between years 2012 and 2015. All subjects underwent the analysis of CDH1 genetic variants (rs16260 and rs9929218) by real-time polymerase chain reaction (PCR) genotyping. The results showed that CA and CA + AA genotypes of CDH1 single nucleotide polymorphism (SNP) rs16260 were significantly reverse associated with EGFR mutation type (Adjusted odds ratio (AOR) = 0.43, 95% CI = 0.20-0.92 and AOR = 0.46, 95% CI = 0.22-0.96, respectively) in female lung adenocarcinoma patients. Moreover, the significantly reverse associations between CA and CA + AA genotypes of CDH1 rs16260 and EGFR hotspot mutations, namely L858R mutation and exon 19 in-frame deletion, were also demonstrated among female patients. Besides, CA + AA genotype of CDH1 rs16260 was noted significantly reverse associated with the tumor sizes (OR = 0.31, 95% CI = 0.12-0.80; p = 0.012). In conclusion, our results suggested that CDH1 variants are significantly reverse associated with mutation of EGFR tyrosine kinase, especially among the female patients with lung adenocarcinoma. The CDH1 variants might contribute to pathological development in lung adenocarcinoma.

Association of endothelial nitric oxide synthase (eNOS) polymorphisms with EGFR-mutated lung adenocarcinoma in Taiwan.

EGFR mutation of Non-small cell lung cancers (NSCLC) was predominantly seen in Asian population and it was considered as a predictor of responsiveness. Eendothelial nitric oxide synthase (eNOS) plays a vital role in chronic inflammation and carcinogenesis. In this study, we aimed to explore the association between the genetic polymorphisms of eNOS (-786T/C and 894 G/T) and EGFR mutation in patients with lung adenocarcinoma. A total of 277 patients with diagnosed lung adenocarcinoma were recruited between years 2012 and 2015. All study subjects underwent the analysis of eNOS genetic variants (-786 T/C and 894 G/T) using real-time polymerase chain reaction (PCR) genotyping. Our results showed that, among the 277 patients, variant types (GT + TT) of eNOS 894 G/T polymorphism were significantly positively correlated with EGFR mutation type, specifically exon 19 in-frame deletion. With the subgroup of EGFR L858R mutation, variant genotypes (GT + TT) of eNOS 894 G/T were significantly associated with lymph node invasion. Moreover, in silico analysis indicated that eNOS 894 G/T altered the eNOS expression. In conclusion, our study showed that eNOS 894 G/T variants were significantly associated with EGFR mutation types of lung adenocarcinoma, specifically exon 19 in-frame deletion. This may be utilized as a prediction of tumor invasiveness and therapy responsiveness.

Variations in the AURKA Gene: Biomarkers for the Development and Progression of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a liver malignancy and a major cause of cancer mortality worldwide. AURKA (aurora kinase A) is a mitotic serine/threonine kinase that functions as an oncogene and plays a critical role in hepatocarcinogenesis. We report on the association between 4 single nucleotide polymorphisms (SNPs) of the AURKA gene (rs1047972, rs2273535, rs2064836, and rs6024836) and HCC susceptibility as well as clinical outcomes in 312 patients with HCC and in 624 cancer-free controls. We found that carriers of the TT allele of the variant rs1047972 were at greater risk of HCC compared with wild-type (CC) carriers. Moreover, carriers of at least one A allele in rs2273535 were less likely to progress to stage III/IV disease, develop large tumors or be classified into Child-Pugh class B or C. Individuals with at least one G allele at AURKA SNP rs2064863 were at lower risk of developing large tumors or progressing to Child-Pugh grade B or C. Our results indicate that genetic variations in the AURKA gene may serve as an important predictor of early-stage HCC and be a reliable biomarker for the development of HCC.

Plasma levels of the tissue inhibitor matrix metalloproteinase-3 as a potential biomarker in oral cancer progression.

Oral cancer is the most common malignancy with poor prognosis and is the fourth most common cancer in men in Taiwan. The tissue inhibitor of metalloproteinase-3 (TIMP3) acts as a tumor suppressor gene by inhibiting the growth, angiogenesis, migration, and invasion of cancer cells. However, few studies have examined the association of plasma TIMP3 levels with oral squamous cell carcinoma (OSCC), and the role of plasma TIMP3 levels in OSCC progression is still unclear. We measured the plasma TIMP3 levels of 450 OSCC patients and 64 healthy controls by using a commercial enzyme-linked immunosorbent assay. We also analyzed TIMP3 mRNA levels of 328 OSCC patients and 32 normal tissues from The Cancer Genome Atlas (TCGA) dataset. Our results revealed that plasma TIMP3 levels were significantly lower in patients with OSCC than in healthy controls (p < 0.001). Moreover, plasma TIMP3 levels in patients with OSCC were significantly associated with the tumor stage and tumor status but not with the lymph node status, metastasis, and cell differentiation. To verify our findings, we also examined TCGA bioinformatics database and discovered similar results for the association with the pathological stage of OSCC. In conclusion, our results suggest that plasma TIMP3 is a potential biomarker for predicting the tumor stage and T status in patients with OSCC.

Association between survivin genetic polymorphisms and epidermal growth factor receptor mutation in non-small-cell lung cancer.

Survivin is an anti-apoptotic protein that is implicated in the regulation of apoptosis and cell cycle in various types of cancers. The current study explored the effect of survivin gene polymorphisms and EGFR mutations in non-small-cell lung carcinoma (NSCLC) patients. A total of 360 participants, including 291 adenocarcinoma lung cancer and 69 squamous cell carcinoma lung cancer patients, were selected for the analysis of three survivin genetic variants (survivin -31, +9194, and +9809) by using real-time PCR genotyping. The results indicated that GC+CC genotypes of survivin -31 were significant association with EGFR mutation in lung adenocarcinoma patients (adjusted odds ratio=3.498, 95% CI = 1.171-10.448; p<0.01). Moreover, The GC+CC genotypes of survivin -31 were associated with EGFR L858R mutation but not in exon 19 in-frame deletions. Furthermore, among patients in exon 19 in-frame deletions, those who have at least one polymorphic G allele of survivin -31 have an increased incidence to develop late-stage when compared with those patients homozygous for C/C (OR, 4.800; 95% CI, 1.305-17.658). In conclusion, our results showed that survivin genetic variants were related to EGFR mutation in lung adenocarcinoma patients and might contribute to pathological development to NSCLC.

The Clinical Significance of the Insulin-Like Growth Factor-1 Receptor Polymorphism in Non-Small-Cell Lung Cancer with Epidermal Growth Factor Receptor Mutation.

The insulin-like growth factor 1 (IGF1) signaling pathway mediates multiple cancer cell biological processes. IGF1 receptor (IGF1R) expression has been used as a reporter of the clinical significance of non-small-cell lung carcinoma (NSCLC). However, the association between IGF1R genetic variants and the clinical utility of NSCLC positive for epidermal growth factor receptor (EGFR) mutation is not clear. The current study investigated the association between the IGF1R genetic variants, the occurrence of EGFR mutations, and clinicopathological characteristics in NSCLC patients. A total of 452 participants, including 362 adenocarcinoma lung cancer and 90 squamous cell carcinoma lung cancer patients, were selected for analysis of IGF1R genetic variants (rs7166348, rs2229765, and rs8038415) using real-time polymerase chain reaction (PCR)genotyping. The results indicated that GA + AA genotypes of IGF1R rs2229765 were significantly associated with EGFR mutation in female lung adenocarcinoma patients (odds ratio (OR) = 0.39, 95% confidence interval (CI) = 0.17-0.87). Moreover, The GA + AA genotype IGF1R rs2229765 was significantly associated with EGFR L858R mutation (p = 0.02) but not with the exon 19 in-frame deletion. Furthermore, among patients without EGFR mutation, those who have at least one polymorphic A allele of IGF1R rs7166348 have an increased incidence of lymph node metastasis when compared with those patients homozygous for GG (OR, 2.75; 95% CI, 1.20-2.31). Our results showed that IGF1R genetic variants are related to EGFR mutation in female lung adenocarcinoma patients and may be a predictive factor for tumor lymph node metastasis in Taiwanese patients with NSCLC.

Association of intercellular adhesion molecule-1 single nucleotide polymorphisms with hepatocellular carcinoma susceptibility and clinicopathologic development.

Intercellular adhesion molecule-1 (ICAM-1) is a human protein encoded by the ICAM-1 gene and is typically expressed on endothelial cells and immune cells. ICAM-1 is associated with episode, growth, invasion, and metastasis of hepatocellular carcinoma (HCC). However, the association between ICAM-1 genetic variants and the risk of HCC is undetermined. In this study, we investigated the potential associations of ICAM-1 single nucleotide polymorphisms (SNPs) with susceptibility to HCC and its clinicopathological characteristics. A total of 918 participants, including 613 controls participants and 305 patients with HCC, were selected for the analysis of ICAM-1 SNPs (rs3093030, rs5491, rs281432, and rs5498) by using real-time PCR genotyping. After adjusting for covariants of age, sex, and alcohol consumption, 125 smoker patients with HCC carrying at least one G genotype (AG and GG) in rs5498 were observed to have a higher HCC risk compared with 231 smoker control participants carrying the wild-type allele AA (adjusted odds ratio (AOR), 1.713; 95 % confidence interval (CI), 1.091-2.690; P = 0.019). However, patients who possess at least one polymorphic allele of rs5498 are less prone to develop vascular invasive (AOR, 0.309; 95 % CI, 0.103-0.926; P = 0.036). The results suggest that the genetic polymorphism in ICAM-1 rs5498 SNPs with genotype AG and GG is associated with HCC risk among smokers. Moreover, gene and environment interactions of ICAM-1 rs5498 polymorphisms might alter susceptibility to liver cancer. Therefore, ICAM-1 rs5498 may serve as a marker to predict the vascular invasion risk in smoker patients with HCC.

Relationship of Genetic Polymorphisms of the Chemokine, CCL5, and Its Receptor, CCR5, with Coronary Artery Disease in Taiwan.

The chemokine receptor CCR5 polymorphism, which confers resistance to HIV infection, has been associated with reduced risk of cardiovascular disease. However, the association of the chemokine, CCL5, and its receptor, CCR5, polymorphism and coronary artery disease (CAD) in the Taiwanese has not been studied. In this study, 483 subjects who received elective coronary angiography were recruited from Chung Shan Medical University Hospital. CCL5-403 and CCR5-59029 were determined by polymerase chain reaction-restriction fragment length polymorphism. We found that CCL5-403 with TT genotype frequencies was significantly associated with the risk of CAD group (odds ratio = 3.063 and p = 0.012). Moreover, the frequencies of CCR5-59029 with GG or GA genotype were higher than AA genotype in acute coronary syndrome individuals (odds ratio = 1.853, CI = 1.176-2.921, p = 0.008). In conclusion, we found that CCL5-403 polymorphism may increase genetic susceptibility of CAD. CCL5-403 or CCR5-59029 single nucleotide polymorphism may include genotype score and it may predict cardiovascular event.

Fibroblast growth factor receptor 4 polymorphism is associated with liver cirrhosis in hepatocarcinoma.

BACKGROUND: Fibroblast growth factor receptor 4 (FGFR4) polymorphisms are positively correlated with tumor progression in numerous malignant tumors. However, the association between FGFR4 genetic variants and the risk of hepatocellular carcinoma (HCC) has not yet been determined. In this study, we investigated the potential associations of FGFR4 single nucleotide polymorphisms (SNPs) with HCC susceptibility and its clinicopathological characteristics. METHODOLOGY/PRINCIPAL FINDINGS: Four SNPs in FGFR4 (rs1966265, rs351855, rs2011077, and rs7708357) were analyzed among 884 participants, including 595 controls and 289 patients with HCC. The samples were further analyzed to clarify the associations between these gene polymorphisms and the risk of HCC, and the impact of these SNPs on the susceptibility and clinicopathological characteristics of HCC. After adjusting for other covariants, HCC patients who carrying at least one A genotype (GA and AA) at rs351855 were observed to have a higher risk of liver cirrhosis compared with those carrying the wild-type genotype (GG) (OR: 2.113, 95% CI: 1.188-3.831). Moreover, the patients with at least one A genotype were particularly showed a high level of alpha-fetoprotein (AFP). CONCLUSIONS: Our findings suggest that genetic polymorphism in FGFR4 rs351855 may be associated with the risk of HCC coupled with liver cirrhosis and may markedly increase the AFP level in Taiwanese patients with HCC. In addition, this is the first study that evaluated the risk factors associated with FGFR4 polymorphism variants in Taiwanese patients with HCC.

Timosaponin AIII mediates caspase activation and induces apoptosis through JNK1/2 pathway in human promyelocytic leukemia cells.

Timosaponin AIII (TAIII) is a steroidal saponin isolated from Anemarrhena asphodeloides that has been shown to inhibit cell growth and induce apoptosis in cancer. However, the effect of TAIII on acute myeloid leukemia (AML) remains unclear. Here, the molecular mechanism by which TAIII-induced apoptosis affects human AML cells was investigated. The results showed that TAIII significantly inhibited cell proliferation of four AML cell lines (MV4-11, U937, THP-1, and HL-60). Furthermore, TAIII induced apoptosis of HL-60 cells through caspase-3, caspase-8, and caspase-9 activations and PARP cleavage in a dose- and time-dependent manner. Moreover, Western blot analysis also showed that TAIII increased phosphorylation of JNK1/2 and p38 MAPK in a dose-dependent manner. Inhibition of JNK1/2 by specific inhibitors significantly abolished the TAIII-induced activation of the caspase-8. Taken together, our results suggest that TAIII induces HL-60 cell apoptosis through JNK1/2 pathways and could serve as a potential additional chemotherapeutic agent for treating AML.

CD44 gene polymorphisms and environmental factors on oral cancer susceptibility in Taiwan.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is the fourth leading cause of male cancer death in Taiwan. Exposure to environmental carcinogens is the primary risk factor for developing OSCC. CD44, a well-known tumor marker, plays a crucial role in tumor cell differentiation, invasion, and metastasis. This study investigated CD44 single-nucleotide polymorphisms (SNPs) with environmental risk factors to determine OSCC susceptibility and clinicopathological characteristics. METHODOLOGY/PRINCIPAL FINDINGS: Real-time polymerase chain reaction (PCR) was used to analyze 6 SNPs of CD44 in 599 patients with oral cancer and 561 cancer-free controls. We determined that the CD44 rs187115 polymorphism carriers with the genotype AG, GG, or AG+GG were associated with oral cancer susceptibility. Among 731 smokers, CD44 polymorphisms carriers with the betel-nut chewing habit had a 10.30-37.63-fold greater risk of having oral cancer compared to CD44 wild-type (WT) carriers without the betel-nut chewing habit. Among 552 betel-nut chewers, CD44 polymorphisms carriers who smoked had a 4.23-16.11-fold greater risk of having oral cancer compared to those who carried the WT but did not smoke. Finally, we also observed that the stage III and IV oral cancer patients had higher frequencies of CD44 rs187115 polymorphisms with the variant genotype (AG+GG) compared with the wild-type (WT) carriers. CONCLUSION: Our results suggest that gene-environment interactions between the CD44 polymorphisms and betel quid chewing and tobacco smoking increase the susceptibility to oral cancer development. Patients with CD44 rs187115 variant genotypes (AG+GG) were correlated with a higher risk of oral cancer development, and these patients may possess greater chemoresistance to advanced- to late-stage oral cancer than WT carriers do. The CD44 rs187115 polymorphism has potential predictive significance in oral carcinogenesis and also may be applied as factors to predict the clinical stage in OSCC patients.

Impact of MCP-1 and CCR-2 gene polymorphisms on coronary artery disease susceptibility.

Coronary artery disease (CAD) was the second leading cause of death during the last 3 years in Taiwan. Smooth muscle cells, monocytes/macrophages, and endothelial cells produce monocyte chemoattractant protein-1 (MCP-1) within atherosclerotic plaques following binding to the chemokine receptor-2 (CCR-2). Previous studies have well-documented the association between MCP-1 expression and susceptibility to, or clinicopathological features, of CAD. This study investigated the relationships between MCP-1-2518A/G and CCR-2-V64I genetic polymorphisms and CAD in the Taiwanese population. A total of 608 subjects, including 392 non-CAD controls and 216 patients with CAD, were recruited and subjected to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to evaluate the effects of these two polymorphic variants on CAD. Results indicated a significant association between MCP-1 -2548 gene polymorphism and susceptibility to CAD. GG genotypes (OR = 1.629; 95 % CI = 1.003-2.644), or individuals with at least one G allele (OR = 1.511; 95 % CI = 1.006-2.270), had a higher risk of CAD as compared with AA genotypes. Results also revealed that subjects with at least one A allele of the V64I CCR2 gene polymorphism had significantly increased risk of CAD. G allele in MCP-1-2518 might contribute to higher prevalence of atrial fibrillation in CAD patients (OR = 4.254; p < 0.05). In conclusion, MCP-1-2518G and CCR-2 64I gene polymorphisms represent important factors in determining susceptibility to CAD, and the contribution of MCP-1-2518G could be through effects on atrial fibrillation in CAD patients.

Differential expression of glutathione-S-transferase isoenzymes in various types of anemia in Taiwan.

BACKGROUND: Published reports concerning the expression of GST in various anemias including aplastic, hemolytic, iron deficiency and thalassemia anemia has been insufficient. We improved the conventional GST assay by incorporating a chloroform treatment to remove the interference of hemoglobin and evaluated the altered expression of GSTs in various anemias in Taiwan. METHODS: We incorporated a chloroform treatment to eliminate the interference of hemoglobin. Erythrocyte total GST and isoenzymes activities from 35 control subjects and 125 subjects of various anemias, including aplastic, hemolytic, iron deficiency and thalassemia anemias were measured spectrophotometrically. RESULTS: Chloroform treatment did not significantly affect GST activities in erythrocytes of control subjects while the activities of erythrocyte total GST and alpha-GST were significantly increased in all anemic patients (P<0.001). The expression of mu-GST was significantly decreased, although at a less extent, in cases of aplastic, iron deficiency and thalassemia anemia (P<0.05), but pi-GST was not physiologically different in various types of anemia. CONCLUSION: The determination of changes in erythrocyte GST activity is a promising indicator of oxidative stress conditions that occur in various types of anemia. Measurement of GST activity might be useful for the evaluation of prophylactic treatment in trials of antioxidant strategies.

The tumor-growth inhibitory activity of flavanone and 2'-OH flavanone in vitro and in vivo through induction of cell cycle arrest and suppression of cyclins and CDKs.

Natural products, including flavonoids, are suggested to be involved in the protective effects of fruits and vegetables against cancer. However, studies concerning the effect of flavonoids frequently lacked data regarding to flavanones. In this study, we investigated the inhibitory effect of flavanone compounds, including flavanone, 2'-OH flavanone, 4'-OH flavanone, 6-OH flavanone, naringin and naringenin, on cell growth of various cancer cells. We determined that flavanone and 2'-OH flavanone inhibited cell growth of A549, LLC, AGS, SK-Hepl and HA22T cancer cells, while other flavanones showed little or no inhibition. We evaluated growth-inhibitory activity of flavanone and 2'-OH flavanone against highly proliferative human lung cancer cells (A549) via anchorage-independent and -dependent colony formation assay, and further showed that treatment of flavanone resulted in a G1 cell cycle arrest with reduction of cyclin D, E and cyclin-dependent kinase (CDK) 2, while treatment of 2'-OH flavanone led to a G2/M phase accumulation with reduction of cyclin B, D and Cdc2. Moreover, we demonstrated the improvement effect of flavanone and 2'-OH flavanone with anti-cancer drug, doxorubicin, on A549 cells. Finally, flavanone and 2'-OH flavanone were evidenced by its inhibition on the growth of A549 and Lewis lung carcinoma cells in vivo.

Alternation of cytosolic carbonic anhydrase isoenzymes during deciduomatal development in pregnant mice.

OBJECTIVE: To analyze the activity of cytosolic carbonic anhydrases (CAs) during the pre- and postimplantation stages of pregnancy in mice. Furthermore, to investigate the CA activity in mice in which abortion was induced by injection of substance P. DESIGN: Controlled animal experiment. SETTING: University research laboratory. ANIMAL(S): A total of 75 ICR mice (weight between 20-25 g) that showed two consecutive 4-day cycles. INTERVENTION(S): Substance P (2.4 microg/g) or CA inhibitor (100 microg/g), or both, were administered. Decidualized uterine tissues were collected on days 0.5-10.5 after administration. MAIN OUTCOME MEASURE(S): The activity, protein expression pattern, and mRNA level of decidual cytosolic CAs. RESULTS: The abortion induced by injection of substance P led to an aberrant expression of cytosolic CA and a decreased number of embryos. Furthermore, substance P-induced abortion could be effectively inhibited by CA inhibitors. CONCLUSIONS: Cytosolic CAs, especially CA II, may act as negative regulators in implantation, development, and maintenance of the pregnancy and therefore, this information could be further applied in developing therapies for human sterility.

The differential expression of cytosolic carbonic anhydrase in human hepatocellular carcinoma.

Cytosolic carbonic anhydrases (CAs), including CAI, CAII and CAIII are present in normal hepatocytes. This study was aimed to investigate the expression status of CAs in hepatocellular carcinomas (HCC) and cholangiocellular carcinoma (CCC) and the role of tumor progression. The activity, protein expression pattern and messenger RNA of cytosolic CA were analyzed by CA activity analysis, immunoblot and RT-PCR in 60 human hepatocellular carcinomas and 10 human cholangiocellular carcinoma surgical specimens. The in situ distribution of CAI, CAII and CAIII in hepatocellular carcinomas tissues were analyzed by immunohistochemistry. The result showed that in each of 60 human hepatocellular carcinomas and 10 cholangiocellular carcinoma, CA activity and protein expression in tumor area was significantly lower than that of paired adjacent normal tissues (P < 0.01), and mRNA expressions in tumor areas were also reduced (P < 0.001). Furthermore, the immunohistochemical studies have further confirmed this reduction of CAI, CAII and CAIII protein expression in tumor areas. There was a statistically significant reduction in the expression of cytosolic CAII in poorly differentiated cancer (P < 0.001). Furthermore, the reduction of CAI, CAII and CAIII in HCC tumor areas was also revealed in this study and this reduction might promote tumor cell motility and contribute to tumor growth and metastasis.

The aberrant expression of cytosolic carbonic anhydrase and its clinical significance in human non-small cell lung cancer.

This study was designed to elucidate the possible relationship between the expression of cytosolic carbonic anhydrase (CA) and non-small cell lung cancer (NSCLC). The activity and protein expression patterns of carbonic anhydrase I (CAI) and II (CAII) of 70 NSCLC patients were analyzed by CA activity analysis, immunoblotting and immunohistochemical staining. The results showed that the CA activity and protein expression were significantly decreased in both squamous cell carcinoma (SCC) and adenocarcinoma (AD) (P<0.001 and P<0.001). From our study, it was suggested that the reduction of CAI and CAII in both SCC and AD patients may promote tumor cell motility and contribute to tumor growth and metastasis.