Reduced IQGAP2 protein linked to more aggressive esophageal cancer

Reduced levels of the IQ motif-containing GTPase activating protein 2, or IQGAP2, that typically slows down or stops tumor growth were linked to more aggressive tumors and shorter survival in patients with esophageal squamous cell carcinoma (ESCC), according to a study published Aug. 10 in Frontiers in Genetics.

ESCC is an aggressive form of esophageal cancer that’s usually diagnosed at an advanced stage, when treatment options are limited. The cancer caused an estimated 544,100 deaths worldwide in 2020, and survival rates have stayed poor despite treatment with surgery, chemotherapy and radiation, according to the study.

IQGAP2 is a protein that slows tumor growth in a number of other cancers, including those of the liver, prostate, breast and stomach. Unlike a related protein called IQGAP1, which can help tumors grow, IQGAP2 has generally been found to hold cancer growth in check. However, the role of the protein in ESCC is not known to be examined yet.

The study's author, Liangcheng Zhao of The Fifth People's Hospital of Wujiang District in China, analyzed tumor tissue from 236 patients with ESCC. Zhao used gene sequencing and a lab technique called qPCR to measure IQGAP2 levels in each sample. An esophageal cancer cell line was then used to test what happens when cells make more or less IQGAP2 than normal. Cell growth was tracked over several days using a standard lab assay.

Zhao also measured the activity of the cell-signaling pathway mitogen-activated protein kinase (MEK/ERK MAPK), using a protein-detection method called Western blotting. Key results were confirmed in a second, different esophageal cancer cell line to check whether the findings held up across cell types.

Data revealed that IQGAP2 levels were significantly lower in tumor tissue than in nearby healthy tissue across the 236 patients studied. Patients with low IQGAP2 levels were more likely to have larger tumors, cancer that had spread to lymph nodes and more advanced disease stages. Those differences were unlikely to be due to chance, the study noted.

Patients with low IQGAP2 levels also survived for a shorter time than patients with higher levels of the protein, based on a statistical method called Kaplan-Meier analysis that tracks survival over time.

In the lab, cancer cells engineered to make more IQGAP2 grew slower and cells engineered to make less of the protein grew faster. Lowering IQGAP2 also increased activity of the MEK/ERK MAPK pathway and raised the activity of three genes tied to tumor growth and spread, called c-Myc, Cyclin D1 and MMP9.

When the MEK/ERK MAPK pathway was blocked with a separate compound, the extra growth caused by low IQGAP2 disappeared. This action revealed that the pathway, and not some other factor, was driving the effect.

These findings come entirely from lab experiments and tissue samples analyzed at a single hospital. Zhao cautioned that cell culture models do not fully capture the tumor microenvironment or the broader factors that influence how ESCC develops in patients.

He also noted that the findings raise the possibility that restoring IQGAP2 activity, or blocking the MEK/ERK MAPK pathway directly, could eventually be explored as a treatment strategy for ESCC. This idea has not yet been tested in animals or humans and would require substantial additional research before it could be considered for patient care.

Zhao said in the study that the findings add to a growing body of research identifying IQGAP2 as an important regulator of tumor development. Data from the overall study provide as key information for further investigating IQGAP2 as a potential therapeutic target in ESCC.