Somatic mutations can promote malignant transformation of airway epithelial cells and induce inflammatory responses directed against resultant tumors. Tumor-infiltrating T lymphocytes (TIL) in early-stage non-small cell lung cancer (NSCLC) secrete distinct proinflammatory cytokines, but the contribution of these TILs to tumor development and metastasis remains unknown. We show here that TILs in early-stage NSCLC are biased toward IL17A expression (Th17) when compared with adjacent tumor-free tissue, whereas Th17 cells are decreased in tumor infiltrating locoregional lymph nodes in advanced NSCLC. Mice in which and ( ) are deleted from airway epithelial cells develop spontaneous tumors, that share genetic signatures with squamous- (SQ.2b), and adeno- (AD.1) subtypes of human NSCLC. mice globally lacking in ( ) showed decreased tumor latency and increased metastasis. Th17 cells were required for recruitment of CD103 dendritic cells, and adoptive transfer of -sufficient CD4 T cells reversed early tumor development and metastasis in mice. Together, these findings support a key role for Th17 cells in TILs associated with the model of NSCLC and suggest therapeutic and biomarker strategies for human SQ2b and AD1 lung cancer. .

Soluble forms of receptors play distinctive roles in modulating signal-transduction pathways. Soluble CD74 (sCD74) has been identified in sera of inflammatory diseases and implicated in their pathophysiology; however, few relevant data are available in the context of cancer. Here we assessed the composition and production mechanisms, as well as the clinical significance and biological properties, of sCD74 in melanoma. Serum sCD74 levels were significantly elevated in advanced melanoma patients compared with normal healthy donors, and the high ratio of sCD74 to macrophage-migration inhibitory factor (MIF) conferred significant predictive value for prolonged survival in these patients (p = 0.0035). Secretion of sCD74 was observed primarily in melanoma cell lines as well as a THP-1 line of macrophages from monocytes and primary macrophages, especially in response to interferon-γ (IFN-γ). A predominant form that showed clinical relevance was the 25-KDa sCD74, which originated from the 33-KDa isoform of CD74. The release of this sCD74 was regulated by either a disintegrin and metalloproteinase-mediated cell-surface cleavage or cysteine-protease-mediated lysosomal cleavage, depending on cell types. Both recombinant and THP-1 macrophage-released endogenous sCD74 suppressed melanoma cell growth and induced apoptosis under IFN-γ stimulatory conditions via inhibiting the MIF/CD74/AKT-survival pathway. Our findings demonstrate that the interplay between sCD74 and MIF regulates tumor progression and determines patient outcomes in advanced melanoma.

Mechanisms of lung squamous cell carcinoma (LSCC) development are poorly understood. Here, we report that JNK1/2 activities attenuate Lkb1 -deficiency-driven LSCC initiation and progression through repressing ΔNp63 signaling. In vivo Lkb1 ablation alone is sufficient to induce LSCC development by reducing MKK7 levels and JNK1/2 activities, independent of the AMPKα and mTOR pathways. JNK1/2 activities is positively regulated by MKK7 during LSCC development. Pharmaceutically elevated JNK1/2 activities abates Lkb1 dependent LSCC formation while compound mutations of Jnk1/2 and Lkb1 further accelerate LSCC progression. JNK1/2 is inactivated in a substantial proportion of human LSCC and JNK1/2 activities positively correlates with survival rates of lung, cervical and head and neck squamous cell carcinoma patients. These findings not only determine a suppressive role of the stress response regulators JNK1/2 on LSCC development by acting downstream of the key LSCC suppresser Lkb1 , but also demonstrate activating JNK1/2 activities as a therapeutic approach against LSCC.

We investigated the therapeutic effect of oculo-acupuncture on dogs induced with acute hepatic injury. Hepatic injury was induced by intraperitoneal injection with carbon tetrachloride (CCl(4)) in 8 mongrel dogs (4 females and 4 males, aged 2 to 4 years). The dogs were divided into the control group (4 dogs) and the experimental group (4 dogs). The experimental group was treated with oculo-acupuncture at the liver/gallbladder regions plus the zhong jiao region of the eye after the induction of hepatic injury. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma glutamyl transpeptidase (GGT) activities were measured in both control and experimental groups. The serum AST, ALT, and GGT activities in the experimental group were decreased as compared to those in the control group. The significant differences were detected on the third day (AST, p < 0.05), second day (ALT, p < 0.05) and third day (GGT, p < 0.05) in the experimental group, respectively. Oculo-acupuncture alleviated acute liver damage induced by carbon tetrachloride in dogs was also confirmed by histopathological examination. We concluded that oculo-acupuncture at the liver/gallbladder regions plus the zhong jiao region was effective in the recovery of dogs from hepatic injury in a CCl(4)-induced model.