L523S, an RNA-binding protein as a potential therapeutic target for lung cancer

Abstract

Approaches to vaccine-based immunotherapy of human cancer may ultimately require targets that are both tumour-specific and immunogenic. In order to generate specific antitumour immune responses to lung cancer, we have sought lung cancer-specific proteins that can be targeted for adjuvant vaccine therapy. By using a combination of cDNA subtraction and microarray analysis, we previously reported the identification of an RNA-binding protein within the KOC family, L523S, to be overexpressed in squamous cell cancers of the lung. We show here that L523S exhibits significant potential for vaccine immunotherapy of lung cancer. As an oncofetal protein, L523S is normally expressed in early embryonic tissues, yet it is re-expressed in a high percentage of nonsmall cell lung carcinoma. The specificity of L523S expression in lung cancer was demonstrated by both mRNA and protein measurements using real-time PCR, Western blot, and immunohistochemistry analyses. Furthermore, we show that immunological tolerance of L523S is naturally broken in lung cancer patients, as evidenced by detectable antibody responses to recombinant L523S protein in eight of 17 lung pleural effusions from lung cancer patients. Collectively, our studies suggest that L523S may be an important marker of malignant progression in human lung cancer, and further suggest that treatment approaches based on L523S as an immunogenic target are worthy of pursuit.

IMP3 is a novel biomarker for adenocarcinoma in situ of the uterine cervix: an immunohistochemical study in comparison with p16INK4a expression

“…Previous data has shown that IMP3 expression is not tumor specific. 3,4,9 It is more likely that IMP3 is a marker of malignancy. IMP3 overexpression has been reported in carcinomas of the stomach, colon, A large body of epidemiologic and molecular data has shown that high-risk types of the human papillomavirus (HPV) are the etiologic agents for most cases of endocervical glandular neoplasia.…”

“…Insulin-like growth factor-II mRNA-binding protein 3 (IMP3) known in previous publications as L523S or KOC (K-homologous domain containing protein overexpressed in cancer), 3,4 is a newly identified oncofetal RNA-binding protein that binds to mRNAs such as insulin-like growth factor-II (IGF-II) transcripts. IMP3 is expressed during embryogenesis but not in most adult tissues.…”

“…A monoclonal antibody specific for IMP3 has been used successfully with routine immunohistochemical methods to study overexpression of IMP3 protein in a number of malignant tumors. 3,4 Recently, it has been demonstrated that IMP3 expression is an independent prognostic factor for renal cell carcinoma. 9 Cyclin-dependent kinase (CDK) inhibitor p16 INK4a protein is a member of the INK4 family of cell cycle regulatory proteins and specifically inhibits the formation of cyclin D1-CDK4/6 complexes [10][11][12] which control the activity of retinoblastoma tumorsuppressor protein pRb by phosphorylation.…”

IMP-3 is a novel progression marker in malignant melanoma

“…13,16,17 Increased levels of IMP-3 have been identified in pancreatic carcinoma, renal cell carcinoma, germ cell neoplasms, ovarian carcinoma, and extrapulmonary small-cell carcinoma, as well as high-grade neuroendocrine carcinoma, squamous cell carcinoma, and adenocarcinoma of the lung. [16][17][18][19][20][21] Additionally, IMP-3 was shown to be a prognostic marker in patients with renal cell carcinoma, with lack of expression in the primary tumor predicting longer metastases-free survival. 22 IMP-3 expression increases with grade of dysplasia in pancreatic ductal epithelium and with tumor stage in pancreatic carcinoma.…”

“…22 IMP-3 expression increases with grade of dysplasia in pancreatic ductal epithelium and with tumor stage in pancreatic carcinoma. 19 Finally, two studies demonstrating inhibition of cell proliferation after knockdown of IMP-3 in human K562 leukemia cells 15 and an immunogenic response to administration of IMP-3 in lung cancer patients 21 show promise for IMP-3 as a potential target molecule for cancer therapy.…”