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...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 G412mRNA 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 MEGFand CA9 mRNAs, but the tumor-associated changes in mRNA levels of VEGFand CA12 showed a significant inverse relationship. CONCLUSION: Our results indicate that CA9and 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.展开更多
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 con...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.展开更多
基金Supported by the Grants From Sigrid Juselius Foundation, from Finnish Cultural Foundation and Finnish Dental Society from the National Institutes of Health (DK40163, GM34182, and GM53405)from Slovak Grant Agency (2/2025) from the Slovak Government (Cancer Genomics SP 51/0280800) and from Bayer Corporation
文摘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 G412mRNA 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 MEGFand CA9 mRNAs, but the tumor-associated changes in mRNA levels of VEGFand CA12 showed a significant inverse relationship. CONCLUSION: Our results indicate that CA9and 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.
基金Supported by the Sigrid Jusélius Foundation,the Academy of Finland,the Medical Research Funds of Tampere University Hospital and Helsinki University Hospital,and Jane and Aatos Erkko Foundation
文摘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.
