Androgen receptor roles in the liver: Homeostasis and cancer.

摘要

The liver is the largest visceral organ and is highly responsible for systemic homeostasis. Androgen and the androgen receptor (AR), and corresponding downstream signals (Androgen/AR) play a pivotal role in many of the liver's functions. There is already a significant body of literatures that documents Androgen/AR signals are involved in liver cancer and non-cancer related liver diseases. However, conflicts or inconsistencies are common. With the ability to use a conditional knockout animal model, we were able to re-examine these conflicts.This thesis is divided into several components: The introduction section Androgen/AR roles in hepatocarcinogenesis and cancer metastasis and potential therapies and applications. Finally, I discussed the perspectives and significance of this thesis.In Chapter 1, it discussed the classical Androgen/AR signals and nonclassical androgen/AR biological functions. In addition, I discuss the normal liver functions as well as the carcinogensis process and malignant cancer progression from immunology aspect. This section covered the inflammatory signals that cause to pre-malignant liver steatosis, as well as inflammation role in the cancer progression.In Chapter 2, it discussed the AR roles in hepatocarcinogenesis. I found that AR could promote carcinogen-induced carcinogenesis through p53 mediated cellular ROS and DNA repairing system. In Chapter 3, it described that AR has opposite function in the advanced stage of hepatocellular carcinoma. I found AR plays a tumor suppressor role through inhibition of p38 phosphorylation and ablation of MMP9 production in the advanced cancer. In Chapter 4, I've added in another work that discussing androgen/AR signals in the liver homeostasis, as well as a review of present literatures on the androgen/AR signal in hepatitis and non-cancer diseases. I extended the findings described in chapter 2 and 3 into preclinical trials. In Chapter 5, I perspective a hypothesis that suppression of AR in the tumorigenesis state, yet, restoration of AR in the advanced state of cancer development could benefit therapeutic outcome. I consistently found that targeting on AR using ASC-J9, AR degradation compound, reduced tumorigenicity. On the other hand, the combination therapy using Sorafenib and expression of AR in the metastasis cancer model improved survival and increased the number of metastasis free mice.Finally, in Chapter 6, I discussed the significance of this thesis in the field, as well as the potential applications in the cancer therapies. I believe the results of current and future studies will expand our knowledge of hepatology and will, therefore, facilitate the design of new therapeutic regimens for fatal liver disease.