Dr. Min Li

New research led by scientists at The University of Texas Health Science Center at Houston (UTHealth) and Baylor College of Medicine could aid efforts to diagnose and treat one of the most lethal and hard-to-treat types of cancer.

In the EMBO Molecular Medicine journal, the investigators report that they have identified a new molecular mechanism that contributes to the spread of malignant tumors in the pancreas. The hope is that drugs could one day be developed to block this pathway.

Most people with pancreatic cancer die within one to two years of diagnosis, and this form of cancer is expected to claim 38,460 lives in the United States this year. There are currently no effective tests for early detection and no effective therapies for the fast-spreading form.

The study focused on the previously established link between zinc and pancreatic cancer and sought to identify a molecular mechanism responsible for the elevated levels found in human and animal cells. Zinc is an essential trace element and small amounts are important for human health.

“We were the first to show that zinc transporter ZIP4 was a marker for pancreatic cancer,” said Dr. Min Li, the study’s senior author and associate professor in the Vivian L. Smith Department of Neurosurgery. “We knew there was a link, but we didn’t know what it was.”

Li is on the faculty of The University of Texas Graduate School of Biomedical Sciences at Houston, which is a joint venture of UTHealth and The University of Texas MD Anderson Cancer Center.

Zinc levels are regulated by ZIP4, which acts as a master switch, and the researchers designed experiments to determine what happens when the switch is flipped on, Li said.

In an animal model of pancreatic cancer, the scientists observed how the initiation of ZIP4 triggered the activation of two downstream genes, which in turn accounts for the increased tumor growth. Scientists describe this as a signaling cascade.

“We have recently demonstrated a novel biological role for the zinc transporter ZIP4 in pancreatic cancer; however, the molecular pathway controlling this phenomenon remains elusive. This study provides a comprehensive mechanism for ZIP4-mediated pancreatic cancer growth involving the activation of a transcription factor CREB and an oncogenic miR-373, and reduction in key tumor suppressor genes,” said Dr. Yuqing Zhang, co-first author of the study.

Dr. Jingxuan Yang, co-first author and research scientist in the Department of Neurosurgery, said, “Our findings in this study define a novel signaling axis promoting pancreatic cancer growth, providing potential mechanistic insights on how a zinc transporter functions in cancer cells and may have broader implications as abnormal zinc concentration in the cells play an important role in many other diseases.”

“The results we reported in this study may help the design of future therapeutic strategies targeting the zinc transporter and microRNA pathways to treat pancreatic cancer,” said Dr.  Xiaobo Cui, study co-first author and postdoctoral research fellow.

Co-authors include: Dr. Yong Chen, Vivian Zhu, and Dr. John Hagan, of UTHealth; Drs. Huamin Wang, Paul Chiao, and Craig Logsdon, of The University of Texas MD Anderson Cancer Center; Sally Hodges, Dr. William Fisher, Dr. Charles Brunicardi, Dr. Changyi Chen, and Dr. Qizhi Yao, of Baylor College of Medicine; Dr. Martin E. Fernandez-Zapico, of the Mayo Clinic; Dr. Xianjun Yu, of Fudan University in Shanghai, China; and Dr. Jing Fang, of the Chinese Academy of Sciences in Shanghai.

The study titled “A novel epigenetic CREB-miR-373 axis mediates ZIP4-induced pancreatic cancer growth” received support from National Institutes of Health Grants (R01CA138701, R21CA133604), and the William and Ella Owens Medical Research Foundation.

-Rob Cahill, Office of Public Affairs, Media Relations