The aberrant expression of cytosolic carbonic anhydrase and its clinical significance in human non-small cell lung cancer
Introduction
Carbonic anhydrase (CA) is a family of metalloenzymes that catalyze the equilibration of CO2 and carbonic acid. They have been detected in almost all types of tissues with 14 different isoforms and the distribution patterns of these isoenzymes are different from each other [1], [2], [3], [4]. In the aspect of CA function, respiration (CO2 transport and excretion) and ion transport are the two most extensively investigated areas and have been studied primarily on the systemic level. For example, the importance of erythrocyte and vascular CA in the transportation of CO2 in the extracellular fluid and its excretion across the respiratory epithelium have been demonstrated, and the role of CA in systemic mechanisms of ion regulation in extracellular fluid has been studies and used to address the importance of CA function in ion transport [5].
Several studies [6], [7] using either animal models or isolated perfuse lungs showed that inhibition of CA activity significantly reduces the quantity of CO2 exchange. Among the various CA isozymes located in the lung, carbonic anhydrase I (CAI) is present in the lung cellular homogenate [5] and pulmonary arterial endothelial cells [8] and recently, Fleming et al. [9] identified carbonic anhydrase II (CAII) in type II pneumocytes. Because of the unique location, it was speculated that CAII is involved in pulmonary functions such as regulation of fluid secretion and facilitation of CO2 elimination [9]. It has been shown that CA participates in the provision of bicarbonate substrate for cell growth and is involved in several biological processes, including ureagenesis, gluconeogenesis, lipogenesis, and brain metabolism [10]. Furthermore, the expression patterns of CAI and CAII and action of specific CA inhibitor have been most frequently investigated in a variety of tumor cells and cell lines [11]. Both CAI and CAII are significantly less expressed in colorectal tumors [12], [13], but overexpressed in nervous system tumors [14], [15] and pancreatic tumors [16]. Merely with these findings, it is difficult to define a clear-cut relationship between the expressions of CA isozymes in normal and malignant cells. Furthermore, to our knowledge, there is no report concerning the role of cytosolic CAI/CAII in non-small cell lung cancer (NSCLC) has been published yet.
This study was designed with the aim to elucidate the possible relationship between the cytosolic CAI/CAII and non-small cell lung cancer.
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Patients and tissue samples
The study group consisted of 70 NSCLC patients, including 55 males and 15 females, aged between 36 and 82 year-old and the mean age is 65.9 year-old. NSCLC was diagnosed histologically in surgically resected tissues. A total of 70 resected tumors were obtained from the Veterans General Hospital, Taichung, Taiwan. Classification on histological type, pathological stage, and tumor-node-metastasis of these tumor samples were determined according to the criteria of the American Joint Committee on
Results
Tumors from 70 NSCLC patients, including 38 squamous cell carcinomas (SCCs), 26 adenocarcinomas (ADs) and six mixed carcinomas, were used in CA activity assay and immunoblot analysis (Table 1). Since the tumors specimens were obtained from lobectomy or pneumonectomy, very few of stage IV tumors were available for this study. In this study, 55 (79%) men and 15 (21%) women were enrolled, meaning a significantly higher incidence in male than in female. Furthermore, 36 of the study subjects (56%)
Discussion
Recently, many studies support that the expression of CAIX and CAXII is elevated in some malignant tumor tissues including breast cancer [23], colon cancer [24], [25], lung cancer [26], and other malignancies [27], [28]. These investigations have also shown that the hypothetical pH sensing functions of CA isoenzymes may be associated with histidine residues in their catalytic center outside the cell as well as with internal histidines in the cytoplasmic domains [29]. The fact that CAIX and
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