Rabbit Anti-Human TRIB2 (a.a. 151-250) Polyclonal antibody

Introduction: The majority of pulmonary carcinoid (PC) tumors can be cured by surgical resection alone, but a significant proportion of patients experience recurrence. As PC is insensitive to conventional chemotherapy, further clarification of the molecular mechanisms of metastasis is needed in order to develop targeted therapeutics. Methods: We performed comprehensive whole-exome sequencing (WES) of primary tumors and corresponding normal lung tissues from 14 PC patients (including 4 patients who developed postsurgical distant metastasis) and RNA sequencing of primary tumors from 6 PC patients (including 4 patients who developed postsurgical distant metastasis). Exon array-based gene expression analysis was performed in 25 cases of PC. Results: We identified a total of 139 alterations in 136 genes. MUC6 and SPTA1 were recurrently mutated at a frequency of 21% (3/14) and 14% (2/14), respectively. Mucin protein family genes including MUC2, MUC4 and MUC6 were mutated in a mutually exclusive manner in 36% (5/14). Pathway analysis of the mutated genes revealed enrichment of genes involved in mitogen-activated protein kinase (MAPK) signaling, regulation of the actin cytoskeleton and focal adhesion, and transforming growth factor (TGF)-beta signaling. RNA sequencing revealed a total of 8 novel fusion transcripts including one derived from a chromosomal translocation between the TRIB2 and PRKCE genes. All of the 8 fusion genes were detected in primary PCs that had developed metastasis after surgical resection. We identified 14 genes (DENND1B, GRID1, CLMN, DENND1B, NRP1, SEL1L3, C5orf13, TNFRSF21, TES, STK39, MTHFD2, OPN3, MET, and HIST1H3C) up-regulated in 5 PCs that had relapsed after surgical resection. Conclusions: In this study we identified novel somatic mutations and chromosomal rearrangements in PC by examining clinically aggressive cases that had developed postsurgical metastasis. It will be essential to validate the clinical significance of these genetic changes in a larger independent patient cohort.

Hypoxia-inducible factor-1 (HIF-1) and its most important subunit, HIF-1 alpha, plays a central role in tumor progression by regulating genes involved in cancer cell survival, proliferation and metastasis. HIF-1 alpha activity is associated with nuclear accumulation of the transcription factor and regulated by several mechanisms including modulation of protein stability and degradation. Among recent advances are the discoveries that inflammation-induced cytokines and growth factors affect protein accumulation of HIF-1 alpha under normoxia conditions. TNF alpha, a major pro-inflammatory cytokine that promotes tumorigenesis is known as a stimulator of HIF-1 alpha activity. To improve our understanding of TNF alpha-mediated regulation of HIF-1 alpha nuclear accumulation we screened a kinase-specific siRNA library using a cell imaging-based HIF-1 alpha-eGFP chimera reporter assay. Interestingly, this systematic analysis determined that depletion of kinases involved in conventional TNF alpha signaling (IKK/NF kappa B and JNK pathways) has no detrimental effect on HIF-1 alpha accumulation. On the other hand, depletion of PRKAR2B, ADCK2, TRPM7, and TRIB2 significantly decreases the effect of TNF alpha on HIF-1 alpha stability in osteosarcoma and prostate cancer cell lines. These newly discovered regulators conveyed their activity through a non-conventional RELB-depended NF kappa B signaling pathway and regulation of superoxide activity. Taken together our data allow us to conclude that TNF alpha uses a distinct and complex signaling mechanism to induce accumulation of HIF-1 alpha in cancer cells. In summary, our results illuminate a novel mechanism through which cancer initiation and progression may be promoted by inflammatory cytokines, highlighting new potential avenues for fighting this disease.