Open AccessCyclooxygenase‐2/carbonic anhydrase‐IX up‐regulation promotes invasive potential and hypoxia survival in colorectal cancer cells
Author(s) -
Sansone Pasquale,
Piazzi Giulia,
Paterini Paola,
Strillacci Antonio,
Ceccarelli Claudio,
Minni Francesco,
Biasco Guido,
Chieco Pasquale,
Bonafè Massimiliano
Publication year - 2009
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2008.00580.x
Subject(s) - gene knockdown , colorectal cancer , cancer research , transfection , carcinogenesis , biology , western blot , cancer cell , gene expression , cyclooxygenase , hypoxia (environmental) , small interfering rna , cell culture , cancer , microbiology and biotechnology , chemistry , medicine , gene , enzyme , biochemistry , genetics , organic chemistry , oxygen
Inflammation promotes colorectal carcinogenesis. Tumour growth often generates a hypoxic environment in the inner tumour mass. We here report that, in colon cancer cells, the expression of the pro‐inflammatory enzyme cyclooxygenase‐2 (COX‐2) associates with that of the hypoxia response gene carbonic anhydrase‐IX (CA‐IX). The COX‐2 knockdown, achieved by the stable infection of a COX‐2 specific short harpin RNA interference (shCOX‐2), down‐regulates CA‐IX gene expression. In colorectal cancer (CRC) cells, PGE 2 , the main COX‐2 gene products, promotes CA‐IX gene expression by ERK1/2 activation. In normoxic environment, shCOX‐2 infected/CA‐IX siRNA transfected CRC cells show a reduced level of active metalloproteinase‐2 (MMP‐2) that associates with a decreased extracellular matrix invasion capacity. In presence of hypoxia, COX‐2 gene expression and PGE 2 production increase. The knockdown of COX‐2/CA‐IX blunts the survival capability of CRC cells in hypoxia. At a high cell density, a culture condition that creates a mild pericellular hypoxic environment, the expression of COX‐2/CA‐IX genes is increased and triggers the invasive potential of colon cancer cells. In human colon cancer tissues, COX‐2/CA‐IX protein expression levels, assessed by Western blot and immunohistochemistry, correlate each other and increase with tumour stage. In conclusion, these data indicate that COX‐2/CA‐IX interplay promotes the aggressive behaviour of CRC cells.