Screening of tumor-associated antigens based on Oncomine database and evaluation of diagnostic value of autoantibodies in lung cancer.

OBJECTIVES: The purpose of this study is to discover novel tumor-associated antigens (TAAs) to improve the diagnosis of lung cancer (LC). MATERIALS AND METHODS: Oncomine database was used to discover potential TAAs from LC tissues, enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of autoantibodies against TAAs in two independent sets (identification set, n = 368; validation set, n = 1011). RESULTS: Analyses of sera from identification set showed that the sensitivity of autoantibodies against five TAAs (HMGB3, ZWINT, GREM1, NUSAP1 and MMP12) reached 57.1%, 42.4%, 38.0%, 36.4% and 20.7%, with area under ROC curve (AUC) of 0.85, 0.75, 0.71, 0.73 and 0.70, respectively. It also validated the diagnostic performances of these autoantibodies with AUC of 0.72, 0.65, 0.61, 0.64 and 0.64, respectively. Autoantibody against HMGB3 exhibited significantly increased frequency in early LC (53.3%) compared to advanced LC (29.3%) (P < .05). The positive rates of autoantibody against HMGB3 and NUSAP1 in serum of LC patients without distant metastasis were significantly higher than that of distant metastatic LC (P < .05). When each of the three protein biomarkers (CEA, CA125 and CYFRA21-1) was combined with anti-HMGB3 autoantibody, the sensitivity of early LC increased to 72.7%, 63.3% and 75.9% from 36.4%, 13.3% and 27.6%, respectively. CONCLUSION: Autoantibodies against 5 TAAs (HMGB3, ZWINT, GREM1, NUSAP1 and MMP12) might have favorable diagnostic values in LC detection, and autoantibody against HMGB3 has the potential to serve as a serological biomarker in early-stage LC. The combination of protein biomarkers and anti-HMGB3 might contribute to detection of early-stage LC.

Two novel homologs of high mobility group box 3 gene in grass carp (Ctenopharyngodon idella): potential roles in innate immune responses.

High mobility group box 3 (HMGB3) protein is a universal sentinel in the activation of innate antiviral immune responses in mammalian cells of limited tissues. However, the underlying immune functions of HMGB3 responding to viruses and viral/bacterial pathogen-associated molecular patterns (PAMPs) are still unknown in teleosts. In the present study, two novel homologs of grass carp (Ctenopharyngodon idella) HMGB3 (designated as CiHMGB3a and CiHMGB3b) were identified and characterized. Quantitative RT-PCR analysis showed that CiHMGB3a and CiHMGB3b were widely expressed in tissues. The mRNA expressions of CiHMGB3a and CiHMGB3b were induced by grass carp reovirus (GCRV) challenges both in tissues and in cells, and CiHMGB3a played a more active role in antiviral immune responses. Viral PAMP stimulation evidenced that CiHMGB3a and CiHMGB3b mediated immune responses in CIK (C. idella kidney) cells. Interestingly, CiHMGB3a had little impact on bacterial PAMPs (LPS and PGN), whereas CiHMGB3b was critical responding to bacterial PAMPs stimulation. In overexpressions of CiHMGB3a and CiHMGB3b cells, the transcriptional levels of CiHMGB3a, CiHMGB3b, CiTRIF, CiIPS-1, CiIFN-I and CiMx1 were remarkably induced. In addition, CiMyD88 had vital impact on antiviral signaling channels in overexpression of CiHMGB3b cells. Furthermore, 96-well plate staining assay, virus titer test and GCRV quantitative analysis collectively indicated CiHMGB3a and CiHMGB3b exhibited substantial antiviral activity. These results suggest that CiHMGB3a and CiHMGB3b exert important functions in antiviral immune responses by TLRs and RLRs signaling pathways. Taken together, current study provides the first evidence that HMGB3 participates in broad antiviral and antibacterial immune responses in teleosts.

TEL (ETV6)-AML1 (RUNX1) initiates self-renewing fetal pro-B cells in association with a transcriptional program shared with embryonic stem cells in mice.

The initial steps involved in the pathogenesis of acute leukemia are poorly understood. The TEL-AML1 fusion gene usually arises before birth, producing a persistent and covert preleukemic clone that may convert to precursor B cell leukemia following the accumulation of secondary genetic "hits." Here, we show that TEL-AML1 can induce persistent self-renewing pro-B cells in mice. TEL-AML1+ cells nevertheless differentiate terminally in the long term, providing a "window" period that may allow secondary genetic hits to accumulate and lead to leukemia. TEL-AML1-mediated self-renewal is associated with a transcriptional program shared with embryonic stem cells (ESCs), within which Mybl2, Tgif2, Pim2, and Hmgb3 are critical and sufficient components to establish self-renewing pro-B cells. We further show that TEL-AML1 increases the number of leukemia-initiating cells that are generated in collaboration with additional genetic hits, thus providing an overall basis for the development of novel therapeutic and preventive measures targeting the TEL-AML1-associated transcriptional program.