Expression of carbonic anhydrase 9, a potential intrinsic marker of hypoxia, is associated with poor prognosis in oesophageal squamous cell carcinoma

Abstract

Carbonic anhydrase 9 (CA9) is a protein to be upregulated under exposure to hypoxic conditions. Hypoxic conditions are known to be associated with resistance to chemotherapy and radiotherapy, and with poor cancer prognosis. We examined CA9 expression in surgical specimens from oesophageal squamous cell carcinoma (ESCC) patients (n ¼ 127) using immunohistochemistry and real-time RT -PCR. We also examined CA9 expression and cell proliferation in ESCC cell lines (TE-2, TE-8 and TE-15) and an immortalised human oesophageal cell line (CHEK-1) using real-time RT -PCR, Western blotting, ELISA and MTT assay. Immunohistochemistry, high expression of CA9 was found in 63 of the 127 primary tumour specimens and was correlated with poor outcome (P ¼ 0.0003) and more aggressive/less favourable clinicopathological parameters (tumour size (P ¼ 0.0235), tumour depth (Po0.0001), regional lymph node metastasis (P ¼ 0.0031), distant lymph node metastasis (P ¼ 0.0077), stage (Po0.0001) and blood vessel invasion (P ¼ 0.006)). In vitro, CA9 expression in cultured cells and culture medium was also induced by hypoxia (Po0.01). CA9 is correlated with poor prognosis and malignant phenotype in patients with ESCC, and was upregulated by hypoxia. It is suggested that control of CA9 expression might improve the effectiveness of chemotherapy and radiotherapy in ESCC.

Clinicopathological significance of carbonic anhydrase 9, glucose transporter-1, Ki-67 and p53 expression in oral squamous cell carcinoma

“…since, in many studies, patients with cA9 expression had a poor outcome, cA9 has been believed to be a negative prognostic factor (8,(10)(11)(12)(13)(14)(15)(16). on the contrary, among these solid tumors, there is one study indicating that patients with cA9 expression had a better outcome in renal cell carcinoma (9).…”

“…this is a cancer-associated antigen recognized by antibodies, produced by cervical cancer or renal cell carcinoma cells, and is expressed in normal tissues of gastrointestinal tract membranes, bile ducts (7) and skin (unpublished data). recently, many research groups have reported its expression not only in renal cell carcinoma and cervical cancer, but also in bladder cancer, non-small cell lung cancer, breast cancer, head and neck cancer, esophageal cancer, stomach cancer, large intestine cancer, bile duct cancer, sarcoma and chronic myeloid leukemia (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). yoshikawa et al prepared mousederived renal cell carcinoma cells expressing human cA9 antigen.…”

Carbonic anhydrase IX correlates with survival and is a potential therapeutic target for neuroblastoma

“…HIF-1alpha, CAIX and GT-1 (glucose transporter-1) are well-established prognostic markers in solid cancers 26 . The hypoxia-dependent expression of CAIX has been described for many solid tumors, including gastric cancer 26,27 , breast cancer 28 , prostate cancer 14 , colon cancer 29 , oral squamous cell cancer 16 , esophageal cancer 30,31 , where it is associated with malignant phenotype 31 , adverse clinicopathological factors 18 , tumor cell dissemination 29,32,33 and poor survival 15,16,26,30,31 . Carbonic anhydrase IX has been shown to be involved in numerous pathological processes including tumorgenicity 16 and was suggested to be involved in malignant transformation 34 .…”

“…Its expression in gastric cancer is associated with increased invasion, supporting the hypothesis that increased CAIX expression may contribute to invasion and thus advanced disease and tumor progression 34 . The presence of CAIX has also been linked with poorer survival/prognosis in several other solid tumors 15,16,26,30,31 . In neuroblastoma, a previous study has shown that CAIX is expressed at significantly higher levels in tumors from patients with adverse clinicopathological and biological factors 18 .…”

MAPKAP Kinase 2 Overexpression Influences Prognosis in Gastrointestinal Stromal Tumors and Associates with Copy Number Variations on Chromosome 1 and Expression of p38 MAP Kinase and ETV1

“…Detailed information about all applied antibodies is provided in Supplementary Table S1. Expressions of ETV1, pp38, pMSK1, and MAPKAPK2 were evaluated by light microscopy on full slides and scored as described previously (18,19): an immunostaining score [immunohistochemistry (IHC) score: 0-300] was calculated as the product of the staining intensity [1 (weak), 2 (moderate), or 3 (strong) expression] and the staining rate (percentage of positive tumor cells, 0%-100%). Tumors with scores exceeding the median were considered showing high expression, tumors equal or below the median as showing low expression.…”