Reverse signaling by semaphorin 4C elicits SMAD1/5- and ID1/3-dependent invasive reprogramming in cancer cells. Gurrapu Sreeharsha,Franzolin Giulia,Fard Damon,Accardo Massimo,Medico Enzo,Sarotto Ivana,Sapino Anna,Isella Claudio,Tamagnone Luca Science signaling Semaphorins are a family of molecular signals that guide cell migration and are implicated in the regulation of cancer cells. In particular, transmembrane semaphorins are postulated to act as both ligands ("forward" mode) and signaling receptors ("reverse" mode); however, reverse semaphorin signaling in cancer is relatively less understood. Here, we identified a previously unknown function of transmembrane semaphorin 4C (Sema4C), acting in reverse mode, to elicit nonconventional TGF-β/BMP receptor activation and selective SMAD1/5 phosphorylation. Sema4C coimmunoprecipitated with TGFBRII and BMPR1, supporting its role as modifier of this pathway. Sema4C reverse signaling led to the increased abundance of ID1/3 transcriptional factors and to extensive reprogramming of gene expression, which suppressed the typical features of the epithelial-mesenchymal transition in invasive carcinoma cells. This phenotype was nevertheless coupled with burgeoning metastatic behavior in vivo, consistent with evidence that Sema4C expression correlates with metastatic progression in human breast cancers. Thus, Sema4C reverse signaling promoted SMAD1/5- and ID1/3-dependent gene expression reprogramming and phenotypic plasticity in invasive cancer cells. 10.1126/scisignal.aav2041

Hypoxia and hypoxia-inducible factor 1 repress SEMA4B expression to promote non-small cell lung cancer invasion. Jian Hong,Liu Bin,Zhang Jie Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine Sema domain of semaphorin 4B (SEMA4B), which is an interacting protein of LNM35, plays an important role in lung cancer invasion. However, the regulation mechanism of this protein is completely unknown. Here, we report that hypoxia and hypoxia mimic reagent could downregulate the expression of SEMA4B in human non-small cell lung cancer (NSCLC) lines. We provide evidences that SEMA4B is a direct target of hypoxia-inducible factor 1 (HIF-1). Silencing the expression of HIF-1α in cancer cells by RNA interference abolished hypoxia-repressed SEMA4B expression. Using luciferase reporter assay, we showed that HIF-1α recognized a hypoxia-responsive element (HRE) of SEMA4B gene, which is required for HIF-1-repressed SEMA4B expression. Moreover, ectopic expression of SEMA4B abolished invasion of hypoxia-induced NSCLC cells. Taken together, these data would shed novel insights on the mechanisms for invasion of hypoxia-induced NSCLC cells. 10.1007/s13277-014-1651-4

CLCP1 interacts with semaphorin 4B and regulates motility of lung cancer cells. Nagai H,Sugito N,Matsubara H,Tatematsu Y,Hida T,Sekido Y,Nagino M,Nimura Y,Takahashi T,Osada H Oncogene We previously established a highly metastatic subline, LNM35, from the NCI-H460 lung cancer cell line, and demonstrated upregulation of a novel gene, CLCP1 (CUB, LCCL-homology, coagulation factor V/VIII homology domains protein), in LNM35 and lung cancer specimens. In this study, we focused on the potential roles of that gene in cancer metastasis. First, we established stable LNM35 RNAi clones, in which CLCP1 expression was suppressed by RNAi, and found that their motility was significantly reduced, although growth rates were not changed. Next, in vitro selection of a phage display library demonstrated that a phage clone displaying a peptide similar to a sequence within the Sema domain of semaphorin 4B (SEMA4B) interacted with LNM35. Immunoprecipitation experiments confirmed interaction of CLCP1 with SEMA4B, regulation of CLCP1 protein by ubiquitination and proteasome degradation enhanced in the presence of SEMA4B. These results are the first to indicate that CLCP1 plays a role in cell motility, whereas they also showed that at least one of its ligands is SEMA4B and that their interaction mediates proteasome degradation by CLCP1. Although the physiological role of the interaction between CLCP1 and SEMA4B remains to be investigated, this novel gene may become a target of therapy to inhibit metastasis of lung cancers. 10.1038/sj.onc.1210183