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

Rebecca Graumann,Iván Roa,Alejandro H Corvalán,Gabriella A Di Capua,Christine Liao,Gareth I Owen,Uwe Zangemeister-Wittke,Annemarie Ziegler,Juan E Oyarzún,Iris Delgado,Marcos A Vásquez,Paola Casanello,Jorge A Brañes,Kwong-Kwok Wong

doi:10.1371/journal.pone.0177244

Abstract

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.

Highlights

Teneurins (Ten-M/ODZ) are highly conserved pair-rule proteins with fundamental roles in embryonic development [1,2,3,4], in particular as regulators of neuronal pathfinding within the central nervous system [4,5,6,7]
The intracellular domain (ICD) of some Teneurins can be cleaved upon homophilic interactions and translocate to the nucleus [14], where it could function in transcriptional control [15]
Ten-1 ICD translocates to the nucleus and colocalizes with the methylation-dependent repressor MBD1, which is consistent with the postulated role of Teneurins in controlling gene expression

Summary

Introduction

Teneurins (Ten-M/ODZ) are highly conserved pair-rule proteins with fundamental roles in embryonic development [1,2,3,4], in particular as regulators of neuronal pathfinding within the central nervous system [4,5,6,7]. Teneurins can undergo dimerization mediated by covalent bridging between adjacent cysteine residues in their extracellular domains [11]. This interaction is essential for homophilic binding during targeted recognition and selective cell-cell adhesion between neighboring neurons [12,13], a process that can guide neuronal connectivity and might drive neuronal regeneration. The intracellular domain (ICD) of some Teneurins can be cleaved upon homophilic interactions and translocate to the nucleus [14], where it could function in transcriptional control [15]. Current data point to a functional interdependence of Teneurins and cytoskeletal components

Methods

Results

Discussion

Conclusion