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Carbonic anhydrase enzymes Ⅱ, Ⅶ, Ⅸ and Ⅻ in colorectal carcinomas

World Journal of Gastroenterology 2016年第36期22卷 8168-8177页

作者： Pia Viikil? Antti J Kivel? Harri Mustonen Selja Koskensalo Abdul Waheed William S Sly Jaromir Pastorek Silvia pastorekova Seppo Parkkila Caj Haglund School of Medicine University of Tampere and Fimlab Ltd Tampere University Hospital Department of Surgery University of Helsinki and Helsinki University Hospital Department of Biochemistry and Molecular Biology Saint Louis University School of Medicine Centre of Molecular Medicine Institute of Virology Slovak Academy of Sciences Research Programs Unit Translational Cancer Biology University of Helsinki

AIM To investigate expression of four alpha-carbonic anhydrases(CAs) in colorectal carcinomas(CRC) and compare the results with patients' survival.METHODS Colorectal carcinoma samples from 539 CRC patients and control tissues were arranged as tissue microarrays and analyzed with antibodies against CA Ⅱ, CA Ⅶ, CA Ⅸ, and CA Ⅻ. Intensity and extent of staining were both scored from 0 to 3 in each sample. These enzyme expression levels were then correlated to patients' survival and clinicopathological parameters, which were tumor differentiation grade and stage, site of tumor, patients' age, and gender. Kaplan-Meier analysis and Cox regression hazard ratio model were used to analyze survival data. RESULTS CA Ⅱ and CA Ⅻ staining intensities correlated with patients' survival in that higher expression indicated poorer prognosis. In Cox regression analysis one unit increase in the CA Ⅱ intensity increased the hazard ratio to 1.19 fold(CI: 1.04-1.37, P = 0.009). A significant correlation was also found when comparing CA Ⅻ staining intensity with survival of CRC patients(HR = 1.18, 95%CI: 1.01-1.38, P = 0.036). The extent of CA Ⅻ immunostaining did not correlate to the patients' survival(P = 0.242, Kaplan-Meier analysis). A significant interaction between age group and extent of the CA Ⅱ staining was found. Increased extent of CA Ⅱ had a significant hazard ratio among patients 65 years and older(1.42, 95%CI: 1.16-1.73, P = 0.0006). No correlations were found between CA Ⅶ(intensity P = 0.566, extent P = 0.495, Kaplan-Meier analysis), or CA Ⅸ(intensity P = 0.879, extent P = 0.315, KaplanMeier analysis) immunostaining results and survival, or the other parameters. CONCLUSION The present findings indicate that CA Ⅱ and CA Ⅻ could be useful in predicting survival in CRC.

关键词： Biomarker Carbonic anhydrase Colorectal cancer Immunohistochemistry Prognosis Survival

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Expression of von Hippel-Lindau tumor suppressor and tumor-associated carbonic anhydrases IX and XII in normal and neoplastic colorectal mucosa

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World Journal of Gastroenterology 2005年第17期11卷 2616-2625页

作者： Antti J. Kivela Seppo Parkkila Juha Saarnio Tuomo J. Karttunen Jyrki Kivela Anna-Kaisa Parkkila Maria Bartosova Vojtech Mucha Michal Novak Abdul Waheed William S. Sly Hannu Rajaniemi Silvia pastorekova Jaromir Pastorek Department of Anatomy and Cell Biology University of Oulu Finland Institute of Medical Technology University of Tampere and Tampere University Hospital Finland Department of Surgery University of Oulu Finland Department of Pathology University of Oulu Finland Institute of Dentistry University of Helsinki and Central Military Hospital Finland Department of Neurology Tampere University Hospital Finland Center of Molecular Medicine Institute of Virology Slovak Academy of SciencesBratislavaSlovak Republic Institute of Neuroimmunology Slovak Academy of Sciences BratislavaSlovak Republic Edward A. Doisy Department of Biochemistry and Molecular Biology Saint Louis University School of Medicine Missouri

AIM: To analyze possible relationships between CA ⅠⅩ/CA Ⅻ and pVHL expression in normal and neoplastic colorectal mucosa.METHODS: Immunohistochemical staining of 42 tissue specimens obtained from 17 cancer patients was performed to evaluate the distribution and semi-quantitatively assess the levels of CA ⅠⅩ, CA Ⅻ and pVHL. VHL mRNAs from 14 fresh-frozen tumors was amplified by RT-PCR and subjected to sequencing. CA9 and CA12 mRNA levels were analyzed by semi-quantitative RT-PCR in comparison with VEGFas an indicator of hypoxia that uncouples the pVHL control.RESULTS: Tumor tissues were associated with a borderline increase of CA ⅠⅩ staining signal and slight but significant decrease of CA Ⅻ immunoreactivity, whereas no association was found for pVHL. Sequence analysis of RT-PCR-amplified VHL mRNAs revealed no deletions/mutations, suggesting that they were VHL-competent. We did not observe any correlation between pVHL and CA ⅠⅩ/CA Ⅻ proteins as well as between VEGF and CA9 mRNAs, but the tumor-associated changes in mRNA levels of VEGF and CA12 showed a significant inverse relationship.CONCLUSION: Our results indicate that CA9 and CA12 are regulated by different intratumoral factors and that lack of apparent relationship between the levels of CA ⅠⅩ/CA Ⅻ and pVHL cannot be fully assigned to uncoupling of negative regulatory function of pVHL by tumor hypoxia signified by induced VEGF transcription. The interplay between the functional pVHL and CA ⅠⅩ/CA Ⅻ in colorectal tumors seems rather complex and is not evident merely at the expression levels.

关键词：结肠肿瘤直肠肿瘤肿瘤抑制物免疫组织化学基因表达

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