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et al. ; Melanoma is a highly metastatic and malignant skin cancer having poor rates of patient survival. Since the incidence of melanoma is steadily increasing in the population, finding prognostic and therapeutic targets are crucial tasks in cancer. The dioxin receptor (AhR) is required for xenobiotic-induced toxicity and carcinogenesis and for cell physiology and organ homeostasis. Yet, the mechanisms by which AhR affects tumor growth and dissemination are largely uncharacterized. We report here that AhR contributes to the tumor-stroma interaction, blocking melanoma growth and metastasis when expressed in the tumor cell but supporting melanoma when expressed in the stroma. B16F10 cells engineered to lack AhR (small hairpin RNA for AhR) exacerbated melanoma primary tumorigenesis and lung metastasis when injected in AhR+/+ recipient mice but not when injected in AhR-/- mice or when co-injected with AhR-/- fibroblasts in an AhR+/+ stroma. Contrary, B16F10 cells expressing a constitutively active AhR had reduced tumorigenicity and invasiveness in either AhR genetic background. The tumor suppressor role of AhR in melanoma cells correlated with reduced migration and invasion, with lower numbers of cancer stem-like cells and with altered levels of β1-integrin and caveolin1. Human melanoma cell lines with highest AHR expression also had lowest migration and invasion. Moreover, AHR expression was reduced in human melanomas with respect to nevi lesions. We conclude that AhR knockdown in melanoma cells requires stromal AhR for maximal tumor progression and metastasis. Thus, AhR can be a molecular marker in melanoma and its activity in both tumor and stromal compartments should be considered. ; Spanish Ministry of Economy and Competitiveness (MINECO; SAF2008-00462, BFU2011-22678, RD06/0020/1016 and RD12/ 0036/0032) and Junta de Extremadura (GR10008) to P.M.F.-S.; Spanish MINECO (SAF2009-07172, RD06/0020/0001 and RD12/0036/0002) and Spanish Association Against Cancer (AECC) to X.R.B. M.C.-T. was a FPI fellow from the Spanish Ministry of Science and Innovation. All Spanish funding is cosponsored by the European Union FEDER program. ; Peer Reviewed

Nearly half of the human genome is made of transposable elements (TEs) whose activity continues to impact its structure and function. Among them, Long INterspersed Element class 1 (LINE-1 or L1) elements are the only autonomously active TEs in humans. L1s are expressed and mobilized in different cancers, generating mutagenic insertions that could affect tumor malignancy. Tumor suppressor microRNAs are ∼22nt RNAs that post-transcriptionally regulate oncogene expression and are frequently downregulated in cancer. Here we explore whether they also influence L1 mobilization. We show that downregulation of let-7 correlates with accumulation of L1 insertions in human lung cancer. Furthermore, we demonstrate that let-7 binds to the L1 mRNA and impairs the translation of the second L1-encoded protein, ORF2p, reducing its mobilization. Overall, our data reveals that let-7, one of the most relevant microRNAs, maintains somatic genome integrity by restricting L1 retrotransposition. ; European Research Council (ERC) ERC-2009-StG 243312 ; French National Research Agency (ANR) ANR-11-LABX-0028-01 ANR-15-IDEX-01 ; Centre National de la Recherche Scientifique (CNRS) 3546 ; University Hospital Federation (FHU) OncoAge ; MINECO PEJ-2014-A-31985 SAF2015-71589-P ; MINECO by European Regional Development Fund SAF2015-71589-P ; Spanish Government RYC-2016-21395 ; Career Integration Grant-Marie Curie FP7-PEOPLE-2011-CIG-303812

Haiyun Zhang,1,* Yujie Liu,2,* Kehan Xu,2,* Kai Mao,1 Weidong Han,1 Feifan Xu,1 Wei Wan,2 Yajun Sun3 1Department of Laboratory Medicine, The Sixth People's Hospital of Nantong, Jiangsu 226000, People's Republic of China; 2Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, People's Republic of China; 3Department of Laboratory Medicine, The Fourth People's Hospital of Nantong, Jiangsu 226000, People's Republic of China*These authors contributed equally to this workCorrespondence: Yajun Sun; Wei WanDepartment of Laboratory Medicine, The Fourth People's Hospital of Nantong, Chenggang Road, Jiangsu 226000, People's Republic of ChinaEmail yajun_sun1@163.com; wei_wan66@163.comIntroduction: Amphiphysin 1 (AMPH-1) is involved in endocytosis, and its expression is upregulated in osteosarcoma compared with osteofibrous dysplasia.Methods: We investigated the role of AMPH-1 in osteosarcoma cells via both gain-of-function and loss-of-function experiments.Results: Knockdown of AMPH-1 in osteosarcoma cells promoted cell cycle progression and cell proliferation and attenuated apoptosis. Notably, silencing AMPH-1 increased osteosarcoma progression in a mouse tumor model. The results obtained upon AMPH-1 knockdown and AMPH-1 overexpression indicates that AMPH-1 is involved in regulating MEK/ERK signaling.Conclusion: These data suggest that AMPH-1 plays an important role in osteosarcoma and may represent a novel therapeutic target for osteosarcoma treatment.Keywords: AMPH-1, osteosarcoma, ERK signaling pathway

Ya He,1,2 Zhihai Wang,1 Chuan Liu,1 Zhitao Gong,1 Yanshi Li,1 Tao Lu,1 Guohua Hu1 1Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; 2Department of Otolaryngology Head and Neck Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China Purpose: Several PCDH genes were shown to be downregulated or silenced in carcinomas and act as candidate tumor suppressor genes. However, the functions of PCDH17 in nasopharyngeal carcinoma (NPC) remain unclear. Here, we investigated the PCDH17 promoter methylation status and its impact on the expression and functions of PCDH17 in NPC. Patients and methods: To determine the mRNA levels and promoter methylation status of PCDH17 in NPC cell lines as well as 42 NPC patient specimens, we performed reverse transcription PCR, methylation-specific PCR, and bisulfite genome sequencing. The effects of ectopic PCDH17 expression in NPC cell lines were determined by colony formation, cell proliferation, wound healing, in vitro human umbilical vein endothelial cells tube formation, migration, invasion, cell cycle, and apoptosis assays and an in vivo subcutaneous tumor model. Results: PCDH17 expression was almost absent or significantly reduced in 100% of the NPC cell lines (5/5). However, 5-aza-2′-deoxycytidine and trichostatin A treatment restored PCDH17 expression. Promoter methylation was involved in PCDH17 silencing. Ectopic expression of PCDH17 in silenced NPC cells reduced colony formation, cell migration, angiogenesis, VEGF secretion, and tumorigenicity. Conclusion: PCDH17 plays a tumor suppressor role in NPC. PCDH17 methylation may be a tumor-specific event and can be used as an epigenetic biomarker for NPC. Keywords: nasopharyngeal carcinoma, PCDH17, tumor suppressor gene, methylation, epigenetic inactivation

Renal cell carcinoma is an important clinical disease with poorly understood etiology. ELF5 is an epithelial-specific member of the Ets family of transcription factors, characterized by the 80 amino acid Ets domain that binds the purine-rich GGAA/T Ets motif found in the promoter regions of a variety of genes. Since ELF5 is highly expressed in kidney and has been postulated to function as a tumor suppressor, at least in the context of the breast, we investigated its role in kidney cancer. In renal cell carcinoma ELF5 expression was consistently decreased in tumor samples versus normal. ELF5 mRNA was decreased in 94% of lesions tested and ELF5 protein was undetectable in 40/40 kidney-derived carcinomas. Re-expression of the ELF5 gene in 786-O renal carcinoma cells suppressed their tumorigenic capacity in vitro and in vivo. This work is the first to suggest that ELF5 has tumor suppressor activity in the kidney.

Colorectal cancer is a disease caused by genetic and epigenetic changes. Inactivation of tumor suppressor genes and activation of oncogenes are key landmarks in tumor progression. However, the list of tumor suppressor genes and oncogenes is far from complete, even in the case of the tumor types that are best characterized, such as colorectal cancer. Colorectal cancer is the second most frequent cause of cancer-related death in the Western world and is a serious health issue for the European Union. Patients having stage III or IV cancer undergo surgery followed by chemotherapy. However, the clinical management of these patients is far from optimal, and only about 30 % of the patients show an objective response to even the best chemotherapeutic agents available. In this study genome-wide high throughput assays were used to better characterize important aspects of the oncogenic progression such as deregulation of proliferation and aberrant expression caused by epigenetic mechanisms. Because rapid tumor proliferation is associated with poor patient prognosis, here we characterized the transcriptional signature of rapidly proliferating colorectal cancer cells in an attempt to identify genes important to sustain tumor growth and that could be used as novel therapeutic targets. The proliferation rate of 52 colorectal cancer cell lines was determined and genome-wide expression profiling of a subset of these lines was assessed by microarray analysis. The expression of 1,290 genes was significantly correlated with the growth rates of colorectal cancer cells. These included genes involved in cell cycle, RNA processing/splicing and protein transport. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and protoporphyrinogen oxidase (PPDX) were shown to have higher expression in faster growing cancer cells. Importantly, pharmacological and genetic inhibition of GAPDH or PPDX reduced the growth of colon cancer cells in vitro and in vivo. To better understand the mechanisms underlying the profound transcriptional reprogramming ...

Rho guanine exchange factors (GEFs), the enzymes that stimulate Rho GTPases, are deemed as potential therapeutic targets owing to their protumorigenic functions. However, the understanding of the spectrum of their pathobiological roles in tumors is still very limited. We report here that the GEF Vav1 unexpectedly possesses tumor-suppressor functions in immature T cells. This function entails the noncatalytic nucleation of complexes between the ubiquitin ligase Cbl-b and the intracellular domain of Notch1 (ICN1) that favors ICN1 ubiquitinylation and degradation. Ablation of Vav1 promotes ICN1 signaling and the development of T cell acute lymphoblastic leukemia (T-ALL). The downregulation of Vav1 is essential for the pathogenesis of human T-ALL of the TLX clinical subtype, further underscoring the suppressor role of this pathway. ; X.R.B. is supported by grants from the Castilla-León Government (BIO/SA01/15, CSI049U16), Spanish Ministry of Economy and Competitiveness (MINECO) (SAF2015-64556-R, RD12/0036/0002), Worldwide Cancer Research (14-1248), Ramón Areces Foundation, and Spanish Society Against Cancer. L.E. (PI13/00448), A.B. (SAF2013-40922-R, RD12/0036/0054), and M.L.T. (SAF2013-44857-R, RD12/0036/0075) are supported by MINECO grants. Spanish funding is partially supported by the European Regional Development Fund. Open Access funded by Worldwide Cancer Research ; Peer Reviewed