Scientists pinpoint a new molecular mechanism tied to pancreatic cancer

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 it is expected to claim 38,460 lives in the United States in 2013. 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 Min Li, Ph.D., the study’s senior author and associate professor and director of the Cancer Research Program in the Vivian L. Smith Department of Neurosurgery at the UTHealth Medical School. “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.

Scientists pinpoint a new molecular mechanism tied to pancreatic cAncer 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.

Pancreatic cancer is among the worst of all cancers. It is imperative to define the mechanism of this deadly disease. 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 Yuqing Zhang, Ph.D., co-first author of the study.

Pancreatic Cancer Facts

  An estimated 45,220 Americans will be diagnosed with pancreatic cancer in the U.S., and over 38,460 will die from the disease.
  Pancreatic cancer is one of the few cancers for which survival has not improved substantially over nearly 40 years.
  Pancreatic cancer is the 4th leading cause of cancer-related death in the United States.
  Pancreatic cancer has the highest mortality rate of all major cancers. 94% of pancreatic cancer patients will die within five years of diagnosis – only 6% will survive more than five years. 74% of patients die within the first year of diagnosis.
  The average life expectancy after diagnosis with metastatic disease is just three to six months.
  Few risk factors for developing pancreatic cancer are defined. Family history of the disease, smoking, age, and diabetes are risk factors.
  Pancreatic cancer may cause only vague symptoms that could indicate many different conditions within the abdomen or gastrointestinal tract. Symptoms include pain (usually abdominal or back pain), weight loss, jaundice (yellowing of the skin and eyes), loss of appetite, nausea, changes in stool, and diabetes.
  Treatment options for pancreatic cancer are limited. Surgical removal of the tumor is possible in less than 20% of patients diagnosed with pancreatic cancer. Chemotherapy or chemotherapy together with radiation is typically offered to patients whose tumors cannot be removed surgically. Only three drugs are FDA‐approved for the treatment of pancreatic cancer: fluorouracil (5‐FU), gemcitabine (Gemzar®), and erlotinib (Tarceva®).
  Pancreatic cancer is a leading cause of cancer death largely because there are no detection tools to diagnose the disease in its early stages when surgical removal of the tumor is still possible.
  The National Cancer Institute (NCI) spent an estimated $105.3 million on pancreatic cancer research in 2012. This represented a mere 1.8% of the NCI’s approximate $5.8 billion cancer research budget for that year.

Source for statistics: American Cancer Society: Cancer Facts & Figures 2013 and NCI Annual Plan and Budget Proposal for Fiscal Year 2012.

Scientists pinpoint a new molecular mechanism tied to pancreatic cAncer Jingxuan Yang, Ph.D., co-first author and research scientist at the UTHealth Medical School, 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 plays 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 Xiaobo Cui, M.D., Ph.D., study co-first author and postdoctoral research fellow at the UTHealth Medical School.

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

There are two types of pancreatic cancer:

  - Exocrine tumors: This type of cancer forms in the pancreas ducts.

  - Endocrine tumors: These tumors are less common and are almost always benign.

Pancreatic cancer is the 10th most commonly diagnosed cancer in the United States.
An estimated 44,030 new cases of pancreatic cancer developed in 2011.
Risk factors that can increase the chance of developing pancreatic cancer:

-  Smoking cigarettes
-  Alcohol
-  Diabetes
  -  Poor diet

90% of people suffering from pancreatic cancer are 55 years of age and older.

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.


The University of Texas Health Science Center at Houston (UTHealth)

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