Correct understanding of the mechanism for carcinogenesis at the molecular level is necessary for sufficient control of cancer, the leading cause of death among Japanese people. Such understanding is indispensable for development of new cancer diagnosis/treatment methods. In recent years, thorough analysis of RNA including non-coding RNA has been advanced after the end of genome project, and the diverse relationships between carcinogenesis and RNA have been revealed increasingly.
The association of mRNA with AU-rich element (ARE) with carcinogenesis has been drawing attention, and many research groups including us suggested that ARE-mRNA contributes to carcinogenesis when it is exported and stabilized. ARE is an element rich in adenine and uracil present in the 3 'untranslated region of mRNA transcribed mainly from genes involved in cell proliferation such as oncogene. ARE-mRNAs are degraded immediately after transcription in normal cells. However, they are transiently exported and stabilized temporarily by stimulus such as stress. And, when some kinds of carcinogenic stimulus are added to the cells, ARE-mRNA is constantly stabilized and induces cell carcinogenesis. This mechanism of cellular carcinogenesis has been confirmed in a wide variety of cancer cells, and has attracted attention as a new cancer mechanism. It has also become clear that "export and stabilization of ARE-mRNA" can also be found in cells involved in diseases other than cancer, such as inflammatory cells and virus-infected cells.
Recently, it has been found that export and stabilization of ARE-mRNA also plays an important role in adenovirus proliferation, and now we are developing the oncolytic adenoviruses based on a new theoretical foundation different from existing virus. This virus can proliferate in cancer cells where ARE - mRNA is stabilized, resulting in destruction of cancer cells, but it can not proliferate in normal cells and has no effect.
At this laboratory, a systematical education/research, ranging from basics to applied one, will be provided concerning development of new cancer diagnosis/treatment methods making use of the findings from such exploration.
- Yanagawa-Matsuda A, Mikawa Y, Habiba U, Kitamura T, Yasuda M, Towfik-Alam M, Kitagawa Y, Minowa K, Shindoh M, Higashino F. Oncolytic potential of an E4-deficient adenovirus that can recognize the stabilization of AU-rich element containing mRNA in cancer cells. Oncol. Rep.. 41, 954-960 (2019).
- Kuroshima T., Aoyagi M., Yasuda M., Kitamura T., Jehung J.P., Ishikawa M., Kitagawa Y., Totsuka Y., Shindoh M. and Higashino F. Viral mediated stabilization of AU-rich element containing mRNA contributes to cell transformation. Oncogene, 30, 2912-2920 (2011).
- Higashino F., Aoyagi M., Takahashi A., Ishino M., Taoka M., Isobe T., Kobayashi M., Totsuka Y., Kohgo T. and Shindoh M. Adenovirus E4orf6 targets pp32/LANP to control the fate of ARE-containing mRNAs by perturbing the CRM1-dependent mechanism. J. Cell Biol. 170, 15-20 (2005).
- Higashino F., Pipas J.M. and Shenk T. Adenovirus E4orf6 oncoprotein modulates the function of the p53-related protein, p73. Proc. Natl. Acad. Sci. USA 95, 15683-15687 (1998).
- Higashino F., Yoshida K., Fujinaga Y., Kamio K. and Fujinaga K. Isolation of a cDNA encoding the adenovirus E1A enhancer binding protein : A new human member of the ets oncogene family. Nucl. Acids Res. 21, 547-553 (1993).