Superfund Monthly Seminar Series

February 11, 2015 - 12:00pm to 1:00pm

Speaker: Dr. Michael Karin, Project Leader

Presenting the research under the Research Project:
Effects of Superfund Toxicants on Liver Cancer Progenitor Cells

Seminar Title: "Stress and Liver Cancer- the p62 connection

Event Summary

In the Superfund Monthly Program meeting of February, 2015, Dr. Michael Karin (Project 1 Leader) presented his laboratory’s research linking obesity and p62 to liver cancer.

   In the first part of his presentation, Dr. Karin depicted the studies in his lab that explored the relationship between obesity and liver cancer development. Referring to data from epidemiology studies, Dr. Karin informed the audience that obesity increases the risk of many types of cancer by 1.6 fold on average. In particular, obese people with a BMI of 30-35 have a 4.5-fold increased risk of liver cancer.

   To determine the role of obesity in liver carcinogenesis and the underlying mechanism(s), they fed mice a high-fat diet following the initiation of the carcinogen DEN. The results clearly showed that a high-fat diet has a significant impact on liver tumor promotion: Increases in tumor incidence and size were observed in mice fed a high-fat diet compared with mice on a normal diet.

   When they examined signaling pathways related to metabolism and stress, by comparing with the control mice, mice fed a high-fat diet exhibited changes as follows: 1) inhibition of AKT phosphorylation status; 2) activation of both JNK and ERK; 3) inhibition of p38; and 4) activation of STAT3. To clarify the role of STAT3 activation following high-fat feeding, they discovered that TNFR1 knockout mice expressed lower IL-6 levels, accompanied by inhibition of STAT3 and a decrease in cancer development, indicating that TNFR1 and IL-6 are required for obesity-mediated tumor progression.

  In the second part of his talk, Dr. Karin focused on the role of mTOR and p62 in liver tumorigenesis. They first determined the contribution of mTOR to liver cancer development on a high-fat diet by knocking out the Raptor – an essential component for mTOR activities. Surprisingly, the results showed that the liver tumor number was significantly increased, and a high-fat diet further promoted the tumorigenesis process in the absence of Raptor, indicating that mTOR plays a role in liver tumor prevention. However, these results contradict those of the experiments conducted by researchers in Harvard in which liver tumors were paradoxically induced when mTOR was constitutively activated.

   What became interesting is that when mTOR is activated by TSC1 deletion, p62 accumulation was present in the liver. In the case of hypernutrition by means of the high-fat diet, mTOR is activated through the inhibition of AMPK, which in turn activates autophagy, subsequently causing p62 accumulation. They found that in p62 knockout mice, HCC development by DEN along with a high-fat diet was impeded, indicating the requirement of p62 in liver tumorigenesis. Similarly, in the MUP-uPA transgenic mouse model, the absence of p62 leads to decreases in triglycerides, lipid droplets, fibrosis, and tumors. This is consistent with what is found in the clinical study: p62 accumulation correlates with poor diagnosis in HCC patients.

   As an adaptor/scaffold protein, p62 not only recruits aggregates of misfolded proteins to autophagosomes but also interacts with Keap1, which is a negative regulator of Nrf2. In fact, mice that developed HCC following a DEN injection exhibited p62 accumulation, accompanied by increases in nuclear Nrf2 levels. Conversely, in the absence of p62 in the knockout mice, no detectable amount of Nrf2 was present in the nucleus, resulting in inhibition of tumorigenesis.

   Dr. Karin continued to address the importance of p62 from another perspective: Researchers in Harvard found that TSC1 negatively regulates p62, and liver-specific deletion of TSC1 – similar to p62 overexpression – leads to increased fibrogenesis and increased tumor development.

   Dr. Karin concluded that p62 could be a key player in HCC development induced by a high-fat diet, and the underlying mechanism involves p62-mediated Nrf2 activation, which may inhibit senescence and/or promote proliferation of HCC initiating cells, leading to the promotion of HCC development.

    Dr. Karin specially acknowledged Dr. Atsushi Umemura and Dr. Hayato Nakagawa for their contribution to the results he presented here.

 (summarized by Mei-Fei Yueh; reviewed and edited by Koji Taniguchi)

The UCSD Superfund Research Center holds a monthly Seminar Series in which participating laboratories, including Principal Investigators, postdoctoral trainees, and students report on their research plans and progress. The scientific presentations are followed by free discussions. These seminars play an essential role in disseminating data between the laboratories, as well as providing an opportunity for all members of the program to interact on a regular basis.

The seminars are mandatory for supported students of our Training Core and postdoctoral fellows that are supported by the research projects. All the Principal Investigators of our Center are encouraged to attend and there is always at least one representative from each Project and Core. Many collaborative activities, especially those between biomedical and non-biomedical projects, have resulted from these meetings.

Upcoming Events

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Past Events

December 16, 2020 - 12:00pm to 1:00pm

Dr. Julian Schroeder - Project 6

November 18, 2020 - 12:00pm to 1:00pm

Dr. Geoffrey Chang - Project 5

October 21, 2020 - 12:00pm to 1:00pm

Dr. Keith Pezzoli - RTC/CEC

June 17, 2020 - 12:00pm to 1:00pm

Drs. Pamela Mellon & Mohit Jain
Genetics and Metabolomics Core

May 20, 2020 - 12:00pm to 1:00pm

Dr. David A. Brenner - Project 4

April 15, 2020 - 12:00pm to 1:00pm

Dr. Ronald M. Evans/Dr. Tae Gyu Oh

March 18, 2020 - 12:00pm to 1:00pm

Dr. Jack Gilbert - Invited Speaker
“The Microbiome: Linking Soil and Human Health”

February 19, 2020 - 12:00pm to 1:00pm

Drs. Elvira Mennillo & Jacopo Baglieri
Training Core Talks

January 15, 2020 - 12:00pm to 1:00pm

Dr. Michael Karin - Project 1
“NRF2 : much more than a stress response factor”

December 11, 2019 - 12:00pm to 1:00pm

Project 6 - Schroeder



UCSD Superfund Research Center
University of California, San Diego
Pharmacology Department
9500 Gilman Drive, Mail Code 0722
La Jolla, CA 92093-0722