Linking LEDGF/p75 Overexpression With Microsatellite Instability and KRAS Mutations: A Small-Scale Study in Colorectal Cancer

TL;DR

This study shows that LEDGF/p75 is overexpressed in colorectal cancer and is linked to specific gene mutations, suggesting it could be a useful biomarker for more aggressive cancers.

Contribution

The study links LEDGF/p75 overexpression with KRAS and MSH2 mutations in colorectal cancer for the first time.

Findings

LEDGF/p75 was overexpressed in 73.3% of tumor tissues compared to adjacent non-tumor tissues.

Co-overexpression of LEDGF/p75 and UBC13 was observed in all six patients tested.

KRAS and MSH2 mutations correlated with LEDGF/p75 overexpression at 75% and 100%, respectively.

Abstract

Colorectal cancer (CRC) ranks third in men and second in women, with 153,020 new cases and 52,550 deaths in 2023, and with a projected incidence of 2.2 million new cases by 2030 due to lifestyle changes and enhanced diagnostic capabilities. Identification and analysis of new biomarkers, like lens epithelium-derived growth factor splice variant of 75 kDa (LEDGF/p75), which is known to play a crucial role as stress-related oncogene, can make a significant contribution in facilitating early CRC detection.

This study analyzed the expression of LEDGF/p75 and the ubiquitin E2 conjugating enzyme UBC13 in 15 CRC tissue samples and adjacent non-tumor tissues. All patient samples underwent NGS-based mutation analysis beforehand. The western blot technique was used for protein analysis, and the results were further validated using mRNA expression data from 521 patient samples from the TCGA database.

LEDGF/p75 expression was significantly elevated in nearly all tumor tissue samples compared to adjacent tissue (11/15, 73.3%). Additionally, the UBC13 enzyme, a key regulator in the degradation of signaling molecules, was also increased in most tumor tissue samples (9/15, 60.0%). Co-overexpression of LEDGF/p75 and UBC13 was evident in 6/6 patients. Patients with KRAS and MSH2 mutations showed a 75% and 100% correlation with LEDGF/p75 overexpression, respectively.

This study confirms the upregulation of LEDGF/p75 in CRC and shows its correlation with KRAS and MSH2 mutations. The interaction of LEDGF/p75 with DNA damage response proteins may contribute to drug resistance and increased tumor aggressiveness. LEDGF/p75’s potential as a prognostic biomarker independent of lymph node involvement or CEA levels highlights its potential in personalized therapy, and warrants further research into its therapeutic targeting.

Colorectal cancer is a big problem, especially for older adults. It’s the third most common cancer in men and the second most common in women. In 2023, there were over 153,000 new cases and more than 52,000 deaths. In a human body, specific proteins act as biomarkers and can be used to detect the presence of cancer cells (diagnostic biomarker) or cancer progression (prognostic biomarker). Analyzing a new possible biomarker like LEDGF/p75 could help to treat colorectal cancer better.

In our study, we determined the expression level of the protein LEDGF/p75, a protein that protects cells from stress and damage, and UBC13, which contributes to uncontrolled cell growth, in 15 samples of colorectal cancer tissue and compared it to the level in normal tissue from the same patients. The patient tissue was beforehand checked for common mutations by sequencing the DNA. We also analyzed the production of LEDGF/p75 mRNA of 521 patient samples from a database.

We found that LEDGF/p75 was much higher in the cancer tissue (11 out of 15, or 73.3%). Additionally, expression of UBC13 was also higher in most cancer tissues (9 out of 15, or 60.0%). And in every patient with high LEDGF/p75 levels, UBC13 levels were also high.

This study shows that LEDGF/p75 is more active in colorectal cancer and is linked to certain gene mutations (KRAS and MSH2). LEDGF/p75 helps cancer cells survive damage from treatments like chemotherapy by boosting DNA repair. This can backfire by making them more resistant to these treatments, allowing them to keep growing. So, if we find a lot of LEDGF/p75, it could mean the cancer is more aggressive, and doctors can plan better treatments.

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