Proteins of the IQGAP family display complicated and often contradictory activities in tumorigenesis. IQGAP1 has well documented oncogenic potential and IQGAP2 has putative tumor-suppressive function. IQGAP3 is the latest addition to this family and its role in cancer development remains to be defined. Here we demonstrate IQGAP3 expression is markedly increased in lung cancer tissues at both mRNA and protein levels. Overexpression of IQGAP3 promoted tumor cell growth, and migration and invasion, whereas knockdown of IQGAP3 exhibited opposite effects. Moreover, suppression of IQGAP3 in a lung cancer cell line caused a reduction in the tumorigenicity of these cells in lung tissue after intravenous injection. Furthermore, we showed that IQGAP3 is able to interact with ERK1 and enhance its phosphorylation following treatment with EGF. These data suggest that IQGAP3 may contribute to the pathogenesis of lung cancer by modulating EGFR-ERK signaling.

Given the clinical significance of hepatitis B e antigen (HBeAg) seroconversion in chronic hepatitis B virus (HBV) infection, it is critical to elucidate the mechanisms regulating this process. In the present study, we found that the frequency of circulating chemokine (C-X-C motif) receptor 5 (CXCR5)+CD4+ T cells was higher in patients who had achieved HBeAg seroconversion in both cross-sectional ( P < 0.001) and longitudinal ( P = 0.009) studies. These cells were able to produce a significantly higher level of intracellular interleukin 21 (IL-21) after stimulation with HBV peptides in patients with telbivudine-induced HBeAg seroconversion ( P = 0.007). Furthermore, sorted CXCR5+CD4+ T cells from HBeAg seroconverters boosted a higher frequency of antibody against hepatitis B e antigen (anti-HBe)-secreting B cells in coculture assay ( P = 0.011). Of note, the increase in frequency of anti-HBe-secreting B cells was abrogated by soluble recombinant IL-21 receptor-Fc chimera ( P = 0.027), whereas exogenous recombinant IL-21 enhanced this effect ( P = 0.043). Additionally, circulating CXCR5+CD4+ T cells shared similar phenotypic markers, and were positively correlated in frequency with, splenic follicular T helper cells. Conclusion : Circulating CXCR5+CD4+ T cells, by producing IL-21, may have a significant role in facilitating HBeAg seroconversion in patients with chronic HBV infection. (Hepatology 2013;58:1277–1286)

Oxidative stress is a key feature in both chronic inflammation and cancer. P38 regulated/activated protein kinase (PRAK) deficiency can cause functional disorders in neutrophils and macrophages under high oxidative stress, but the precise mechanisms by which PRAK regulates reactive oxygen species (ROS) elimination and its potential impact on CD4+ T helper subset function are unclear. The present study reveals that the PRAK-NF-E2-related factor 2(NRF2) axis is essential for maintaining the intracellular redox homeostasis of T helper 17(Th17) cells, thereby promoting Th17 cell differentiation and antitumor effects. Through mechanistic analysis, we identify NRF2 as a novel protein substrate of PRAK and find that PRAK enhances the stability of the NRF2 protein through phosphorylation NRF2 Serine(S) 558 independent of protein ubiquitination. High accumulation of cellular ROS caused by loss of PRAK disrupts both glycolysis and PKM2-dependent phosphorylation of STAT3, which subsequently impairs the differentiation of Th17 cells. As a result, Prak knockout (KO) mice display significant resistance to experimental autoimmune encephalomyelitis (EAE) but impaired antitumor immunity in a MC38 tumor model. This work reveals that the PRAK-NRF2-mediated antioxidant pathway is a metabolic checkpoint that controls Th17-cell glycolysis and differentiation. Targeting PRAK is a promising strategy for maintaining an active ROS scavenging system and may lead to potent Th17 cell antitumor immunity.

Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) promotes lung tumorigenesis via attenuating p53 stability Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) promotes lung tumorigenesis via attenuating p53 stability

Tumor-specific antigens (TSA) are central elements in the immune control of cancers. To systematically explore the TSA genome, we developed a computational technology called heterogeneous expression profile analysis (HEPA), which can identify genes relatively uniquely expressed in cancer cells in contrast to normal somatic tissues. Rating human genes by their HEPA score enriched for clinically useful TSA genes, nominating candidate targets whose tumor-specific expression was verified by reverse transcription PCR (RT-PCR). Coupled with HEPA, we designed a novel assay termed protein A/G–based reverse serological evaluation (PARSE) for quick detection of serum autoantibodies against an array of putative TSA genes. Remarkably, highly tumor-specific autoantibody responses against seven candidate targets were detected in 4% to 11% of patients, resulting in distinctive autoantibody signatures in lung and stomach cancers. Interrogation of a larger cohort of 149 patients and 123 healthy individuals validated the predictive value of the autoantibody signature for lung cancer. Together, our results establish an integrated technology to uncover a cancer-specific antigen genome offering a reservoir of novel immunologic and clinical targets. Cancer Res; 72(24); 6351–61. ©2012 AACR.

Hemokinin 1 (HK-1) is a substance P-like tachykinin peptide predominantly expressed in non-neuronal tissues. In addition to a prominent function in lymphoid development, recent studies indicate a potential role for HK-1 in immunoregulation. The current study was focused on its action on mature B cells. Despite the negligible effect on its own, HK-1 exhibited a profound influence on B cell activation elicited by several classical signals, including LPS stimulation, BCR cross-linking, and CD40 ligation. Cells therefore showed enhanced proliferation, survival, and CD80/86 expression, and produced more IgM with a higher frequency of Ab-forming cells. Biochemical analysis revealed that HK-1 alone was sufficient to induce the activation of MAPKs and the expression of Blimp-1 and Xbp-1 in B cells. Nevertheless, costimulation with a known B cell activator resulted in much enhanced phosphorylation of MAPKs and transcriptional activation of Blimp-1 and Xbp-1. Overall, these data support that HK-1 provides an important costimulatory signal for B cell activation, possibly through synergistic activation of the MAPK pathway and induction of transcription factors critical for plasmacytic differentiation.