NSP ENCODED RETICULONS ARE NEUROENDOCRINE MARKERS OF A NOVEL CATEGORYIN HUMAN LUNG-CANCER DIAGNOSIS

The NSP gene was recently shown to constitute the prototype of a novel gene family, to be selectively transcribed in neural and endocrine ce lls, and to encode three overlapping proteins, NSP-A, NSP-B, and NSP-C . These proteins were collectively designated reticulons, because they were found to be anchored to membranes of the endoplasmic reticulum t hrough their common carboxy-terminal regions. The goal of the present study was to determine whether the reticulons might be used as markers for neuroendocrine differentiation in human lung tumors. Therefore, t he tissue distribution of the NSP-A protein was studied and expression in human lung tumors was evaluated. Immunohistochemical analysis of n ormal tissues with monoclonal antibodies specifically recognizing the NSP-A protein indicated that NSP-A exhibits a distinct neuroendocrine distribution pattern since it was found to be expressed in a variety o f cells with an established neuroendocrine phenotype but not in cells lacking such features. Results with specimens of a wide variety of pri mary human tumors provided further support for this claim. Immunohisto chemical analysis of primary lung carcinomas revealed that NSP-A was r eadily detectable in small cell lung carcinoma (SCLCs) (8 of 12) and c arcinoid tumors of the lung (3 of 3) but not in nonneuroendocrine non- SCLCs (0 of 10). In 13 of 27 non-SCLCs expressing the neural cell adhe sion molecule and/or neurofilament proteins, however, NSP-A was found to be expressed. Northern blot analysis of human lung carcinoma cell l ines revealed expression of NSP-A- and/or NSP-C-encoding mRNAs in all 18 SCLC cell lines that were studied, except one; however, no expressi on of these mRNAs could be detected in any of the 11 non-SCLC cell lin es tested. The NSP transcript encoding NSP-B was found only in SCLC ce ll line NCI-H82. In conclusion, the results of our studies suggest tha t, in lung tumor cells, expression of NSP-A and most likely also NSP-C is restricted to cells with a neuroendocrine phenotype.