Exploring the role of p73-isoforms during tumor development

The p73 gene was first discovered in 1997 as a family member of p53, and since then this gene has been studied extensively in cancer biology. Among its two main classes of isoforms, TAp73 acts as a tumor suppressor, while in contrast ΔNp73 was shown to act in a dominant negative fashion as an oncogene which opposes the functions of TAp73 and p53. This thesis focuses on further deciphering the role of p73 isoforms in tumor angiogenesis, tumor microenvironment and drug resistance which promote tumor development. Tumor initiation heavily relies on the loss of tumor suppressors or gain of function of oncogenes in tumor cells, subsequently resulting in the production of factors that modulate the tumor microenvironment in favor of tumor progression. Solid tumors commonly have a hypoxic core due to extensive growth in size, thus limiting oxygen levels for tumor cell survival. Tumor cells overcome this via producing angiogenic factors to recruit more blood vessels into the tumor for meeting the oxygen and nutrition demands.

In paper I, we discovered that absence of the tumor suppressor TAp73 leads to increased production of angiogenic factors and tumor angiogenesis. Moreover, this angiogenic response was driven via HIF1α. On the other hand, ΔNp73 showed positive regulation of angiogenic gene expression and angiogenic events.

In paper II, we further verified the role of TAp73 in regulation of the angiogenic chemokine CCL2, where TAp73 suppresses CCL2 expression via regulation of NFκB activity. Additionally, TAp73 deficient tumors favored increased recruitment of tumor supporting macrophages. A negative correlation of TP73 with macrophage markers was also confirmed in several human cancer datasets.

In paper III, we further investigated the role of ΔNp73-mediated regulation of HIF1α stability in normoxia. ΔNp73 was found to positively regulate HIF1α stability via regulation of ECV genes, which are important components of the proteasome mediated HIF1α degradation pathway. Finally, in Paper IV, we addressed ΔNp73’s involvement in drug resistance. Oncogenic ΔNp73 upregulated the expression of multidrug resistance related ABC transporters. Additionally, ΔNp73 deficiency reduced drug efflux capacity of breast cancer cells. The positive correlation of ABC transporters and ΔNp73 was also confirmed in melanoma.

In summary, the findings in this thesis further enlighten the role of p73 isoforms in different aspects of tumor development that support chemoresistance and tumor progression.

List of scientific papers

I. Marina Stantic, Habib A. M. Sakil, Hanna Zirath, Trixy Fang, Gema Sanz, Alejandro Fernandez-Woodbridge, Ana Marin, Evelyn Susanto, Tak W. Mak, Marie Arsenian Henriksson, and Margareta T. Wilhelm. TAp73 suppresses tumor angiogenesis through repression of proangiogenic cytokines and HIF-1α activity. PNAS. 2015, 112, p220-225.
https://doi.org/10.1073/pnas.1421697112

II. Habib A. M. Sakil, Johanna Wolfsberger, Marina Stantic, Trixy Fang, and Margareta T. Wilhelm. TAp73 deficiency enhances CCL2 expression and increase intra-tumoral infiltration of tumor-associated macrophages. [Manuscript]

III. Marina Stantic, Johanna Wolfsberger, Habib A. M. Sakil, and Margareta T. Wilhelm. ΔNp73 enhances HIF-1α protein stability through repression of the ECV complex. [Submitted]

IV. Habib A. M. Sakil, Marina Stantic, Johanna Wolfsberger, Suzanne Egyhazi Brage, Johan Hansson and Margareta T. Wilhelm. ΔNp73 regulates the expression of the multidrug-resistance genes ABCB1 and ABCB5 in breast cancer and melanoma cells. Cellular Oncology. 2017.
https://doi.org/10.1007/s13402-017-0340-x