Graumann, RebeccaDi Capua, Gabriella A.Oyarzún, JuanVásquez, Marcos A.Liao, ChristineBrañes, Jorge A.Roa, IvánCasanello, PaolaCorvalán, Alejandro H.Owen, GarethDelgado, IrisUwe, Zangemeister-WittkeZiegler, Annemarie2017-08-292017-08-292017Graumann R, Di Capua GA, Oyarzún JE, Vásquez MA, Liao C, Brañes JA, Roa I, Casanello P, Corvalán AH, Owen GI, Delgado I, Zangemeister-Wittke U, Ziegler A. Expression of teneurins is associated with tumor differentiation and patient survival in ovarian cancer. PLoS One. 2017 May 4;12(5):e0177244.http://hdl.handle.net/11447/1615http://doi.org/10.1371/journal.pone.0177244Teneurins are a family of highly conserved pair-rule proteins involved in morphogenesis and development of the central nervous system. Their function in adult tissues and in disease is largely unknown. Recent evidence suggests a role for dysregulated expression of Teneurins in human tumors, but systematic investigations are missing. Here, we investigated Teneurin-2 and Teneurin-4 expression in various cancer cell lines and in ovarian tumor tissues. Teneurin-2 and Teneurin-4 were expressed in most of the breast cancer cell lines tested. Teneurin-4 was also detected in ovarian cancer cell lines, and throughout ovarian tumors and normal ovary tissue. Ovarian tumors with low Teneurin-4 expression showed less differentiated phenotypes and these patients had shorter mean overall survival. Similarly, Teneurin-2 expression correlated with overall survival as well, especially in patients with serous tumors. In the various cell lines, 5-Aza-cytidine-induced changes in DNA methylation did not alter expression of Teneurin-2 and Teneurin-4, despite the existence of predicted CpG islands in both genes. Interestingly, however, we found evidence for the control of Teneurin-2 expression by the oncogenic growth factor FGF8. Furthermore, we identified multiple transcript splicing variants for Teneurin-2 and Teneurin-4, indicating complex gene expression patterns in malignant cells. Finally, downregulation of Teneurin-4 expression using siRNA caused a cell-type dependent increase in proliferation and resistance to cisplatin. Altogether, our data suggest that low Teneurin-4 expression provides a growth advantage to cancer cells and marks an undifferentiated state characterized by increased drug resistance and clinical aggressiveness. We conclude that Teneurin-2 and Teneurin-4 expression levels could be of prognostic value in ovarian cancer.24en-USgene expressionPolymerase chain reactionovarian cancerdifferentiated tumorssmall interfering RNAsDNA methylationMalignant tumorsReverse transcriptase-polymerase chain reactionArtículo