Arvo building, auditorium F114, address: Arvo Ylpön katu 34.
Doctoral defence of M.Sc. Elisa Vuorinen
The field of science of the dissertation is Cancer Biology.
The opponent is professor Jukka Westermarck (University of Turku). Professor Anne Kallioniemi acts as the custos.
The language of the dissertation defence is Finnish.
Nuclear import protein KPNA7 and its cargos - diverse roles in the regulation of cancer cell growth, mitosis and nuclear morphology
The nucleus is the defining feature of eukaryotic cells. The nuclear envelope separates the cell into distinct nuclear and cytoplasmic compartments and provides a barrier to the diffusion of macromolecules. To maintain cellular homeostasis and to ensure proper function of molecules, cells require a transport system to actively transfer molecules from one compartment to another. Disturbances in nuclear transport can lead to many diseases including cancer.
Members of the karyopherin alpha protein family of nuclear transporters take care of transporting proteins from the cytoplasm into the nucleus. Karyopherin alpha 7 (KPNA7) is the newest and least studied member of this family. The gene encoding KPNA7 is located in a genomic region that is frequently amplified especially in pancreatic cancer, leading to abnormally high expression of the gene. Genes with similar cancer-specific expression are interesting study targets as they may lead to the discovery of improved diagnosis and treatment tools for cancer.
The aim of this study was to evaluate KPNA7 expression levels in cancer cells and healthy adult tissues, to characterize the effect of KPNA7 expression on cancer cell growth, malignant properties, mitosis and maintenance of nuclear structure and to identify KPNA7 cargo proteins.
Results of this study revealed that KPNA7 is expressed at varying levels in pancreatic and breast cancer cell lines. The highest expression levels were detected in pancreatic cancer cells that have the amplification of the gene in their genome. In contrast, the expression of the gene is almost absent in healthy adult tissues. To probe the consequence of KPNA7 expression to the cancer cells, the gene was silenced in a panel of cancer cell lines. The silencing of the KPNA7 gene led to dramatically reduced proliferation and malignant properties of the cells. In addition, KPNA7 silencing led to disturbed mitosis and abnormal, lobulated nuclei.
These data led to the hypothesis that the reason behind these alterations in cell behaviour is the altered subcellular localization of KPNA7 cargo proteins. Hence, this study aimed at identifying these KPNA7 cargos. Two novel KPNA7 cargos were identified and validated, and were also shown to have growth regulatory roles on pancreatic cancer cells.
Together these results suggest that KPNA7, probably at least partially via its cargo proteins, participates in the regulation of growth and viability of cancer cells. The results also shed light on the contribution of KPNA7 to the regulation of proper mitosis and maintenance of nuclear envelope environment and deepen our understanding on the role of nuclear transfer proteins in cancer pathogenesis.
The dissertation is published in the publication series of Acta Universitatis Tamperensis; 2346, Tampere University Press, Tampere 2018. The dissertation is also published in the e-series Acta Electronica Universitatis Tamperensis; 1851, Tampere University Press 2018.