Abstract. Aiming to identify novel sero-diagnostic markers for neu ro endo c r i ne ca rci nom a s of t he lu ng, t he two-dimensional gel electrophoresis-immunoblot method was used to analyze tumor-associated autoantibodies in patients with small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC). Several autoantigens were revealed and anti-HuC autoantibody was detected only in sera of SCLC patients. Since Hu family proteins including HuC are well-known causes of paraneoplastic encephalomyelitis/ sensory neuronopathy (PEM/SN), the expression of HuC as well as HuD mRNAs and their proteins was studied in 11 lung cancer cell lines. The expression of HuC and HuD mRNAs and proteins was only detected in SCLC-and LCNECderived cells. To validate the existence of anti-HuC and -HuD auto-antibodies, we studied a large number of sera including those from lung cancer patients employing dot blot analysis. Anti-HuC and -HuD autoantibodies were detected only in SCLC cases with or without PEM/SN, and not in the sera of LCNEC patients. The mechanism leading to different anti-HuC and -HuD autoantibody production between SCLC and LCNEC is unclear; however, the results from the present and previous studies suggest that anti-HuC and -HuD autoantibodies are novel differential sero-diagnostic markers for SCLC from LCNEC.
IntroductionLung cancer is the leading cause of cancer-related death worldwide. Based on the presence or absence of cellular neuroendo crine differentiation, lung cancer can be grouped into non-neuroendocrine or neuroendocrine tumors. The former is roughly equal to the non-small cell lung cancer (NSCLC) largely comprising squamous cell carcinoma (SCC) and adenocarcinoma (AD). The latter ranges from low-grade typical carcinoid (TC), intermediate-grade atypical carcinoid (AC), to high-grade small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) (1,2), and the 5-year survival rates for TC, AC, LCNEC, and SCLC were 87, 56, 27, and 9%, respectively (2). Similar results were also reported by Garcia-Yuste et al, and the 5-year survival rates for TC, AC, LCENC, and SCLC were 96, 72, 21, and 14%, respectively (3). These results show that both SCLC and LCNEC are highly malignant and have a similar poor prognosis. Pro-gastrin-releasing peptide (pro-GRP) is a well-known sero-diagnostic marker for SCLC; however, its positive rate is lower in stage I and II (35-45%) than in stage III (55-70%) and IV (70-80%). At present, no specific sero-diagnostic markers for distinguishing SCLC from LCNEC have been reported.Autoantibodies are antibodies detected in the sera of patients with various autoimmune diseases. They are also frequently observed in the sera of patients with various malignancies even in the early stages, and, thus, the possibilities for them to be used as potential tumor markers have been suggested (4-10). Hanash (11) has described that harnessing the immune response to identify novel cancer biomarkers is an attractive strategy, because the immune system performs biological ...