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

Abstract

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 VEGF as 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 CA12are 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.

New insight into the key proteins and pathways involved in the metastasis of colorectal carcinoma

“…The levels of GrB2 and S100A4 were higher in metastases than in primary tumors and the levels of KRT20, KISS1 and EPHB2 were apparently decreased, or even undetectable, in metastases compared with primary tumors in most of the cases, in agreement with the results from previous reports (15,(34)(35)(36).…”

“…CLDN2 is increased in the early phase of carcinogenesis, though is reduced during progression to invasive diseases (14). Most of the gene encoded enzymes necessary for cell growth and metabolism are involved in metastasis, which is consistent with the observation that CA12, a hypoxia-inducible gene, is a marker of good prognosis in invasive breast carcinoma, which has an inverse relationship with VEGF (vascular endothelial growth factor) (15). A low expression of GALNT3 is associated with a poorly differentiated tumor, poor pathological stage and nodal metastases in lung carcinoma patients (16).…”

Hypoxia-inducible factor-1α and -2α are expressed in most rectal cancers but only hypoxia-inducible factor-1α is associated with prognosis

“…It is quite likely that numerous factors act separately to cause tumour growth and spread, and pathways may interact in an as yet undefined manner. A number of these factors have been described to be hypoxia and non-hypoxia dependent, including VHL, COX-2, CA-9, CHOP and ATF4, among many others (Yoshimura et al, 2004;Kivela et al, 2005;Carracedo et al, 2006;Cleven et al, 2007). …”

Gene expression profiling in the submandibular gland, stomach, and duodenum of CAVI-deficient mice

“…They catalyze the reversible reaction: CO 2 þ H 2 O , HCO À 3 þ H þ (Sly and Hu 1995). To date, 16 isoforms have been characterized, 13 of which have been found to be enzymatically active (Hilvo et al 2005;Kivela et al 2005;Lehtonen et al 2004;Pastorekova et al 2004). Since several isozymes are expressed in the same cells and tissues, they may be mutually complementary to each other in physiological processes, and their regulation may be at least partly interconnected (Pan et al 2006).…”