We previously found LOXL4 to be alternatively spliced in an anatomic site-specific manner in tumors involving the serosal cavities. LOXL4 splice variants were predominantly or exclusively expressed in effusion specimens from ovarian and breast carcinoma patients, and were absent in primary carcinomas. In the present study, LOXL4 full-length or splice variants were overexpressed in ES-2 and MDA-MB-231 cells and their invasive and metastatic potential and microRNA expression profile were evaluated. ES-2 cells were further injected into SCID mice ovaries and the extent of tumor progression and metastases formation were compared. We show that both splice variants have a positive effect on the metastatic potential of cells in vitro and on tumor progression in vivo. In contrast, full-length LOXL4 is not pro-metastatic, and may even be considered as a tumor suppressor. In addition, we show that LOXL4 is a possible splicing target of the oncogenic splicing factors SRSF1 and hnRNP A1. In conclusion, our results point to a significant role for LOXL4 alternative splicing in tumor progression.
Bibliographical noteFunding Information:
Acknowledgments The authors wish to thank Prof. Trink for kindly providing the LOXL4 construct. This study was partially supported by the Ber-Lehmsdorf Memorial Fund of the Israeli Cancer Association, the Inger and John Fredriksen Foundation for Ovarian Cancer Research and the Norwegian Cancer Society. Reuven Reich is affiliated with the David R. Bloom Center for Pharmacy and the Brettler Center for Pharmacology, both at the Hebrew University of Jerusalem.
- Alternative splicing
- Breast carcinoma
- Lysyl oxidase-like 4
- Ovarian carcinoma
- Tumor progression