Silencing galectin 1 shrinks liver cancer tumors in mice

Researchers at the UC Davis Comprehensive Cancer Center have shown that inhibiting a specific protein using gene therapy can shrink hepatocellular carcinoma (HCC) in mice. Silencing the protein galectin 1 (Gal1), which is often overexpressed in HCC, also improved the antitumor immune response and increased the number of killer T cells within the tumors. The study was published in Acta Pharmaceutica Sinica B.

We have long known that Gal1 is a biomarker for hepatocellular carcinoma. Gal1 expression in normal tissue is quite low and increases with fatty liver disease, inflammation and liver carcinogenesis. Now, we can see that Gal1 is more than a biomarker -? is a potential therapeutic target.”

Yu-Jui Yvonne Wan, Distinguished Professor in the Department of Pathology and Laboratory Medicine and senior author of the study

HCC, cancer that starts in the liver, is one of the most common cancers in the world. And the numbers are growing, with incidence rates more than tripling since the 1980s. The disease can also be quite fatal: In advanced stages, the five-year survival rate is less than 20 percent.

The Wan lab has spent decades studying liver diseases. this study builds on previous research.

Gal1 is overexpressed in HCC

Gal1 suppresses the immune system from attacking healthy tissues. However, when overexpressed in HCC, it promotes cancer growth and prevents the immune system from attacking the tumor. In this study, the team found that high levels of Gal1 were associated with aggressive disease progression and poor survival. This relationship between elevated Gal1 and poor outcomes has also been observed in HCC patients.

Earlier this year, Wan’s team used gene therapy to increase microRNA-22 (miR-22), a non-coding RNA that regulates gene expression, to study its effect on liver cancer. This approach, led by Ying Hu, research assistant professor in Wan’s lab, showed that miR-22 overexpression reduced liver inflammation, treated HCC, and produced better survival outcomes than Lenvatinib, an FDA-approved drug HCC, in an animal model.

The researchers observed that miR-22 reduced activity for several genes, including Gal1. They decided to investigate whether downregulation of Gal1 could be an important mechanism for how miR-22 treats HCC.

To inhibit Gal1, the lab used a short interfering RNA (siRNA), called Igals1. The siRNA was packaged for delivery to adeno-associated virus 9, which prefers to land in the liver. Just in and around the tumor, Igals1 effectively silenced Gal1 in both the cancer and the stroma, the supporting tissues in and around the tumor.

Silencing Gal1 is a potential cure for liver cancer

“Gal1 silencing reduced HCC tumors, which are extremely difficult to treat,” Wan said. “Furthermore, we found that the treatment reduced Gal1 in the stroma at the tumor border, so it has a large impact on the tumor microenvironment.”

Some adenovirus-delivered gene therapies have been approved by the Food and Drug Administration to treat genetic diseases such as spinal muscular atrophy and hemophilia B. However, few researchers have explored the use of this approach against tumors. The authors believe that this study and other work demonstrate the potential of gene therapy for cancer treatments.

While Gal1 inhibition may be found to benefit HCC patients, this approach may present other opportunities.

Gal1 is overexpressed in many types of cancer, including breast, colon, and lung. In addition, the protein begins to accumulate in diseased livers long before HCC develops. As a result, Gal1 inhibition could be considered for the prevention of HCC.

“Galectin 1 silencing is potentially a breakthrough strategy to fight liver cancer,” said Tahereh Setayesh, the study’s first author and a former postdoctoral researcher in Wan’s lab. Setayesh is currently at Cincinnati Children’s Medical Center. “It offers the potential to treat HCC as well as the promise of prevention, providing a pathway to transformative therapies.”

Additional study authors include Ying Hu, Farzam Vaziri and Dongguang Wei from UC Davis. Xin Chen from the University of Hawaii. and Jinping Lai from Kaiser Permanente Sacramento Medical Center.