Alternative splice variant of actinin-4 specific to small cell lung cancer

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Lung cancer is the leading cause of cancer death in Japan and Western countries. Lung caner can be divided into 4 major histological subtypes including squamous cell carcinoma, adenocarcinoma, large cell carcinoma, and small cell carcinoma (SCLC). SCLC is distinguished from the other 3 histological subtypes (non-SCLC) by its distinct histological appearance and early metastasis to lymph nodes, the central nervous system, bone and other sites. Histopathologically, SCLC is characterized by scant cytoplasm and a high nuclear/cytoplasmic ratio. SCLC cells are known to be fragile and highly susceptible to the mechanical force applied during biopsy procedures. SCLC cells in culture adhere poorly to the plastic surface and often grow in suspension. Based on these observations, we hypothesized that SCLC may contain abnormalities in the actin cytoskeleton, because the status of actin directly affects cellular morphology, solidity, adhesion, and motility. The actin cytoskeleton is regulated by various kinds of actin-binding proteins. We previously isolated β-actinin-4 as a novel actin-binding protein (Honda et al., J. Cell Biol., 140:1383-93, 1998). Increased expression of actinin-4 was associated with cell motility and cancer metastasis (Honda et al., Gastroenterology, in press). Reduced expression of actinin-4 is reportedly associated with cell adhesion abnormalities in neuroblastoma cell lines. We identified a novel alternative splice variant RNA of actinin-4 in human SCLC. Expression of the splice variant was highly specific to SCLC cell lines (10/10), biopsies (3/3) and testis. The variant encoded a peptide with a 3 amino-acid change in exon 8, where the germ-line missense mutation takes place in the familial focal segmental glomerulosclerosis (FSGS) syndrome. The variant protein showed high affinity to filamentous actin polymers and was not localized with cortical actin (Honda et al.,Oncogene, 23:5257-62, 2004). Tumor-associated alternative RNA splicing has gained considerable attention. Expression of the variant actinin-4 was essentially limited to SCLC and testis. Recently, a large number of auto-antigens recognized by the host immune system in cancer patients were found to be molecules expressed exclusively in malignant tissues and the testis. These so-called CT antigens (cancer-testis antigens) have been recognized as good candidate targets for cancer immunotherapy, because the testis is naturally protected from cytotoxic T lymphocytes (CTL). Variant actinin-4 is a potential target molecule for immunotherapy against SCLC.