Study identifies miR122 target sites in liver cancer and links a gene to patient survival

August 22, 2017 by Darrell E. Ward, The Ohio State University
Credit: CC0 Public Domain

A new study of a molecule that regulates liver-cell metabolism and suppresses liver-cancer development shows that the molecule interacts with thousands of genes in liver cells, and that when levels of the molecule go down, which often happens during liver-cancer development, the activity of certain cancer-promoting genes goes up. 

The findings could one day help doctors better predict survival in liver cancer patients and help determine whether the molecule – called microRNA-122
(miR-122) – should be developed as an anticancer drug.

The study, reported in the journal Molecular Cell, was led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) and at Rockefeller University's Howard Hughes Medical Institute.

The researchers sought to biochemically (rather than computationally) define all miR-122 target sites in the liver and hepatocellular carcinoma (HCC), the most common form of liver cancer, and to learn which target were critical for liver cancer development or progression. miR-122 is found almost exclusively in liver cells, where its role includes regulating cholesterol and lipid metabolism. 

The researchers identified more than 11,000 miR-122 binding sites in a mouse model. They further found that:

  • miR-122 targets nearly 4,800 genes in humans;
  • Of these targets, 965 are shared with mice;
  • Of the shared targets, a majority are more highly expressed in HCC tumor tissue from patients;
  • Loss of miR-122 in HCC results in the over-expression of certain cancer-related genes.

Increased levels of three conserved , BCL9, SLC52A2 and STX6 in tumor tissues could predict poor survival of human HCC patients.

"Our goal is to understand how miR-122 regulates liver metabolism and suppresses cancer development, and to identify common targets in humans and mice that may be involved in HCC development," says co-principal investigator and OSUCCC – James researcher Kalpana Ghoshal, PhD, associate professor of pathology. "That knowledge is critical for determining whether this molecule should be developed as a possible therapeutic agent for liver ."

The findings significantly extend the number of miR-122 binding sites identified by earlier studies because the methods used by the investigators identified sites that other techniques miss, Ghoshal adds. (Note: one gene can have multiple microRNA target sites.)

For this study, Ghoshal and her colleagues used a mouse model that lacked miR-122, along with normal mice; tissues and normal tissues from nine HCC patients; and data from 373 HCC patients in The Cancer Genome Atlas Liver Hepatocellular Carcinoma dataset.

Other key findings include:

  • While miR-122 is highly conserved (it's present in from fish to humans), a large proportion of miR-122 targets were species specific;
  • The findings revealed binding sites that earlier studies missed; the consequences of miR-122 binding to the additional sites need to be determined;
  • Human HCC has a core set of conserved miR-122 binding sites.

Explore further: Researchers offer new targets for drugs against fatty liver disease and liver cancer

More information: Joseph M. Luna et al. Argonaute CLIP Defines a Deregulated miR-122-Bound Transcriptome that Correlates with Patient Survival in Human Liver Cancer, Molecular Cell (2017). DOI: 10.1016/j.molcel.2017.06.025

Related Stories

Researchers offer new targets for drugs against fatty liver disease and liver cancer

August 22, 2017
There may no silver bullet for treating liver cancer or fatty liver disease, but knowing the right targets will help scientists develop the most effective treatments. Researchers in Sweden have just identified a number of ...

miR-122: Loss of tiny liver molecule might lead to liver cancer

July 23, 2012
A new study shows that loss of a small RNA molecule in liver cells might cause liver cancer and that restoring the molecule might slow tumor growth and offer a new way to treat the disease.

Study identifies a role for the metabolism regulator PPAR-gamma in liver cancer

April 10, 2017
Liver cancers are a major cause of cancer-related deaths. Large-scale genetic analyses have associated liver cancer with dysregulation of numerous molecular pathways, but disruptions in insulin signaling pathways appear to ...

Anti-sense might make sense for treating liver cancer

January 3, 2012
A new study shows that it is possible to selectively target and block a particular microRNA that is important in liver cancer. The findings might offer a new therapy for this malignancy, which kills an estimated 549,000 people ...

Starving cancer cells by blocking their metabolism

June 14, 2016
Scientists at EPFL have found a way to starve liver cancer cells by blocking a protein that is required for glutamine breakdown—while leaving normal cells intact. The discovery opens new ways to treat liver cancer.

Recommended for you

Cancer risk associated with key epigenetic changes occurring through normal aging process

February 22, 2018
Some scientists have hypothesized that tumor-promoting changes in cells during cancer development—particularly an epigenetic change involving DNA methylation—arise from rogue cells escaping a natural cell deterioration ...

Putting black skin cancer to sleep—for good

February 22, 2018
An international research team has succeeded in stopping the growth of malignant melanoma by reactivating a protective mechanism that prevents tumor cells from dividing. The team used chemical agents to block the enzymes ...

NEJM reports positive results for larotrectinib against TRK-fusion cancer

February 22, 2018
In 2013, the labs of University of Colorado Cancer Center investigator Robert C. Doebele, MD, PhD, and Dana-Farber Cancer Institute investigator Pasi A. Jänne, MD, PhD reported in Nature Medicine the presence of TRK gene ...

New therapeutic gel shows promise against cancerous tumors

February 21, 2018
Scientists at the UNC School of Medicine and NC State have created an injectable gel-like scaffold that can hold combination chemo-immunotherapeutic drugs and deliver them locally to tumors in a sequential manner. The results ...

Five novel genetic changes linked to pancreatic cancer risk

February 21, 2018
In what is believed to be the largest pancreatic cancer genome-wide association study to date, researchers at the Johns Hopkins Kimmel Cancer Center and the National Cancer Institute, and collaborators from over 80 other ...

Similarities found in cancer initiation in kidney, liver, stomach, pancreas

February 21, 2018
Recent research at Washington University School of Medicine in St. Louis demonstrated that mature cells in the stomach sometimes revert back to behaving like rapidly dividing stem cells. Now, the researchers have found that ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.