Expression of teneurins is associated with tumor differentiation and patient survival in ovarian cancer.

Graumann, Rebecca; Di Capua, Gabriella A; Oyarzún, Juan E; Vásquez, Marcos A; Liao, Christine; Brañes, Jorge A; Roa, Iván; Casanello, Paola; Corvalán, Alejandro H; Owen, Gareth I; Delgado, Iris; Zangemeister-Wittke, Uwe; Ziegler, Annemarie (2017). Expression of teneurins is associated with tumor differentiation and patient survival in ovarian cancer. PLoS ONE, 12(5), e0177244. Public Library of Science 10.1371/journal.pone.0177244

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Teneurins 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.

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