Although less often the focus of cancer research, recent studies have hinted at the possible importance of a type of protein known as nuclear transport receptors. Now researchers at Kanazawa University and collaborating institutions in Japan and the US have identified a nuclear transport receptor protein that plays a key role in processes that sustain aggressive head and neck cancers, as well as some of the mechanisms behind these processes.
"Current gene expression network approaches commonly focus on TFs [transcription factors], biasing network-based discovery efforts away from potentially important non-TF proteins," point out Masaharu Hazawa and Richard Wong and their colleagues in the report of their latest results. Taking a different tack, they noted that although abnormalities in nuclear transport receptors and their significance in the progression of cancer were not yet understood, recent studies had identified the importance of a type of nuclear transport receptor named karyopherin-α (KPNA)/importin-α in cell differentiation, whereby immature cells acquire the characteristics and functions of specific mature cell types. Tumors of non-differentiated cells are widely understood to be more aggressive.
Noting the role of KPNA in cell fate determination, Hazawa, Wong and colleagues re-analysed the Cancer Genome Atlas, which identified KPNA4 as most higly expressed subtype of KPNAs in head and neck squamous cancer cells (HNSCCs). Using a green fluorescent protein that had a nuclear localization signal, the researchers then investigated the role of KPNA4. They showed that while this green fluorescent protein would normally then localize in the nucleus, in HNSCCs where they had "knocked down" the gene expressing KPNA4 (so that the protein KPNA4 was not expressed) high levels of the green fluorescent protein remained in the cytoplasm instead. As well as the impact on nuclear transport of molecules with the nuclear localization signal, the researchers were also able to observe how silencing the KPNA4 expressing gene reduced the "cell proliferation, migration ability and resistance to radiation" in HNSCCs.
Further studies revealed not only the role of KPNA4 in repressing differentiation of epithelial cells, but also important transcription factors and signaling pathways controlled by KPNA4-dependent nuclear import systems. In their report the researchers conclude:
Taken together, these results indicate that targeting disease-specifically altered transport systems may serve as promising therapeutic strategies for cancer treatment."
Head and neck squamous cell carcinoma
Squamous cell carcinomas are a non-melanoma type of skin cancer, which are the 5th most commonly occurring cancers worldwide. It is a disease that affects the squamous epithelium - flat cells found lining the skin and mucous membranes. Head and neck squamous cancer affects the mucous cells in the mouth, nose and throat.
Transcription factors read and interpret the genetic code in cells. They bind to specific sequences of DNA and control the rate of transcription of that genetic code to messenger RNA, which then conveys that genetic information in the synthesis of new proteins. A number of cancer-suppressing transcription factors have already been identified.
Nuclear transport receptors
While small molecules can move relatively freely across the cell membrane, larger molecules such as proteins need nuclear transport receptors such as karyopherins/importins to enter or leave the cell. Karyopherins help macromolecules navigate the nuclear pore complexes that act as the gateway to the cell.
In a complex organism like a human most cells undergo several differentiations from the initial immature cell into more specialized mature cells that often have very different structures and functions. The process generally involves the activation of a dormant transcription factor.
Hazawa, Wong and colleagues noticed lower levels of KPNA4 where epithelial differentiation increased. Further tests identified that a particular protein regulated by KPNA4 is ras-responsive binding protein (RREB1), and that the Ras/MAPK signaling was affected. Previous work had already established the role of RREB1 in oncogenic Ras/MAPK signaling. Hazawa, Wong and colleagues found that KPNA4 activates a pathway based on Ras and MAPK proteins by mediating nuclear-transport of the Ras-responsive element-binding protein (RREB1). Furthermore, they identified MAPK-dependent processes that enhance transport activity of KPNA4, in what they describe as a "feed forward" process.
Hazawa, M., et al. (2019) Disease-specific alteration of karyopherin-α subtype establishes feed-forward oncogenic signaling in head and neck squamous cell carcinoma. Oncogene. doi.org/10.1038/s41388-019-1137-3.