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Overexpressed Cancer Testis Antigen Could Reflect Therapeutic Target in Liver Cancer

NEW YORK – A cancer testis antigen called MAGEA3 is overexpressed in aggressive hepatocellular carcinoma and, as its inhibition increases apoptosis, it could represent a therapeutic target, a new analysis has found.

To search for drivers of HCC,­ the most common form of primary liver cancer, researchers from the Icahn School of Medicine at Mount Sinai conducted RNA sequencing on different regions of the same tumor from a dozen patients and focused on the expression of cancer testis antigens, or CTAs. These proteins are usually expressed in male germ cells but are also known to be aberrantly expressed in several tumor types, including HCC.

As they reported in PLOS Genetics on Thursday, the researchers found that the X-located CTA MAGEA3 was differentially expressed among HCCs and linked to poor prognosis. They further noted that MAGEA3 upregulates the protein survivin to inhibit apoptosis, suggesting that targeting MAGEA3 to instead promote apoptosis could be a viable treatment approach for HCC. While there are approved therapies for HCC, they tend to prolong survival by only a few months, the researchers noted.

"MAGEA3 was known to be overexpressed in liver cancer for a while," senior author Augusto Villanueva, an assistant professor at Mount Sinai, said in an email. "However, our study is the first to evaluate its potential role in liver cancer progression and as a novel therapeutic target in this disease."

He and his colleagues collected samples from different parts of the same tumor from 12 patients with HCC for analysis, leading to a total 44 samples. This approach, Villanueva noted, allowed them to compare tumor samples from the same patients that varied in their degree of aggressiveness but avoid the confounding genetic factors that arise when aggressive and less aggressive tumors from different patients are analyzed.

By making those comparisons between high- and low-grade regions of the same tumors, the researchers identified genes that were only expressed or that were more highly expressed in more aggressive tumor regions, including CTAs like MAGEA3 and MAGEA1. Tumors that expressed high levels of X-chromosome-located CTAs were also associated with signatures or markers of poor prognosis such as TP53 mutations or high levels of AFP. Clinical data further indicated increased MAGEA3 expression was itself associated with poor overall survival.

When the researchers knocked down MAGEA3 in four HCC cell lines using short-hairpin RNAs, they found that two of the lines relied on MAGEA3 to reach their full proliferative potential. Additionally, overexpressing MAGEA3 in an HCC mouse model led to a higher liver tumor burden and worse survival.

To further trace the mechanism behind how MAGEA3 influences survival, the researchers conducted RNA sequencing and western blot analysis of an HCC cell line following MAGEA3 knockdown treatment.

This knockdown disrupted gene sets associated with apoptosis and cell viability, colony formation, and growth. After MAGEA3 depletion, there was a decrease in survivin at both the RNA and protein level in the cell lines, suggesting that MAGEA3 inhibition leads to an increase in apoptosis through that decline in survivin levels and pointing to a potential role for MAGEA3 in tumor progression by inhibiting apoptosis.

This suggested to the researchers that MAGEA3 could represent an HCC treatment target. Further, Villanueva noted that since CTAs like MAGEA3 are typically only expressed in male germ cells, its inhibition in a cancer treatment setting may be less likely to lead to toxicity than other treatment approaches. He and his colleagues are next planning to examine strategies to pharmacologically inhibit MAGEA3.