We report the identification of a novel cDNA fragment that shows significantly reduced expression in cancerous tissue compared with paired non-cancerous liver tissue in patients with hepatocellular carcinoma (HCC). The full-length transcript of 1733 bp encodes a protein of 308 amino acids that has all the hallmark features of mitochondrial carrier proteins. We designate the novel protein as HDMCP (HCC-down-regulated mitochondrial carrier protein). The HDMCP orthologs in human, mouse, and rat are found to exhibit close similarity in protein sequence and gene organization, as well as exclusive expression in the liver. Moreover, conserved syntenic regions have been demonstrated at the HDMCP gene locus in the human, mouse, and rat genome. Taken
Hepatocellular carcinoma (HCC)1 is one of the most frequent neoplasms worldwide. It has been suggested that chronic hepatitis B and C virus infection, dietary aflatoxin, alcohol consumption, and hepatic iron overload are the etiological factors for HCC development. However, the pathogenic mechanisms responsible for HCC are still not well defined.Mitochondrial defects caused by altered expression of respiratory chain subunits and glycolytic enzymes, decreased oxidation of NADH-linked substrates, as well as mitochondrial DNA mutations have been proposed to contribute to the development and progression of various cancer types including HCC (1-5). It has long been recognized that the most well known function of mitochondria is the production of ATP through oxidative phosphorylation. During mitochondrial respiration, the transfer of electrons along the respiratory chain in the inner mitochondrial membrane is coupled to the translocation of protons (H ϩ ) from the mitochondrial matrix into the intermembrane space. This process generates a proton electrochemical gradient across the inner mitochondrial membrane, which is known as the proton-motive force. This proton-motive force is used to drive the protons back into the matrix through F 0 F 1 -ATP synthase resulting in the synthesis of ATP (6, 7) . Alternatively, the proton-motive force can also be dissipated by "proton leak" catalyzed by multiple parameters, such as classical uncouplers of oxidative phosphorylation (8, 9), fatty acids (10), and the uncoupling protein 1 (UCP1) of brown adipose tissue (11, 12). The mitochondrial membrane potential (⌬⌿ m ) arises from the net movement of positive charge across the inner mitochondrial membrane, reflecting the balance between processes that contribute to the generation of the proton gradient and those that consume it (7).In the early 1980s, Chen and co-workers (13-17) discovered that relative to the mitochondria in normal cells, those in cancer cells displayed a greater uptake and retention of rhodamine 123, a ⌬⌿ m -dependent staining dye, suggesting that cancer cells generate higher ⌬⌿ m compared with normal cells. This is in agreement with a later report showing that ⌬⌿ m of carcinoma cells is ϳ60 mM higher than that of control epithelial cells (18). However, to date, no real underst...