In a groundbreaking study published in BMC Cancer, researchers have unveiled critical insights into the expression patterns and prognostic impact of two pivotal genes—MLH1 and GPRC5C—in resectable hepatocellular carcinoma (HCC). This work sheds new light on molecular mechanisms that could transform our understanding of liver cancer progression and patient outcomes.

Hepatocellular carcinoma, one of the most common and deadly forms of liver cancer worldwide, often presents challenges in treatment due to its aggressive nature and high rates of recurrence post-surgery. Identifying reliable prognostic biomarkers is therefore crucial for advancing therapeutic strategies and tailoring personalized medicine approaches. Against this backdrop, the study by Lu and colleagues probes the roles of mut-L homolog 1 (MLH1), a key DNA mismatch repair protein, and G-protein coupled receptor C5C (GPRC5C), a less characterized receptor, in HCC biology.

Previous research had implicated MLH1 in cancer initiation and progression, highlighting its frequent loss as a driver of genomic instability. Furthermore, MLH1 was reported to inhibit pancreatic cancer metastasis by downregulating GPRC5C, suggesting a potentially significant interplay between these proteins in tumor dynamics. However, their precise expression profiles and prognostic relevance in hepatocellular carcinoma remained unexplored until now.

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The investigative team analyzed tumor samples and adjacent non-tumoral liver tissues from 230 patients who underwent radical resection for HCC. Using tissue microarray-based immunohistochemical staining, they quantified MLH1 and GPRC5C expression levels, enabling a comprehensive comparison between malignant and normal tissue contexts. This large and well-characterized cohort provides robust statistical power to elucidate the molecular correlations within human liver cancer.

Remarkably, the data revealed opposite expression trends for these two genes: MLH1 protein levels were significantly diminished in HCC tumor tissues relative to adjacent normal liver, whereas GPRC5C expression was elevated in the cancerous samples. This inverse relationship was substantiated by a strong negative correlation coefficient, underscoring the antagonistic roles that MLH1 and GPRC5C likely play in tumor biology.

The researchers further investigated correlations between gene expression and clinically relevant parameters. MLH1 exhibited a negative association with alpha-fetoprotein (AFP) levels, a biomarker frequently elevated in liver cancer patients. Conversely, GPRC5C positivity correlated positively with larger tumor size and the presence of vascular invasion, two key indicators of aggressive disease. These findings suggest that reduced MLH1 and increased GPRC5C expressions might respectively signify more favorable and adverse tumor characteristics.

Survival analysis painted a compelling prognostic picture. Patients with high MLH1 expression enjoyed significantly better overall and disease-free survival outcomes, indicating its protective role in the cancer milieu. On the other hand, elevated GPRC5C corresponded with poorer survival metrics, marking it as a potential oncogenic factor. When adjusting for confounding variables in multivariate models, GPRC5C retained its strong prognostic significance for both overall and disease-free survival, whereas MLH1 remained significant primarily for overall survival.

To validate these clinical associations, the study tapped into the publicly accessible Kaplan-Meier Plotter database, which aggregates survival data from diverse gene expression studies. Consistently, MLH1 expression predicted recurrence-free and progression-free survival, reinforcing its utility as a prognostic biomarker in HCC. GPRC5C, while trending toward negative effects on survival, showed less statistical significance in this broader dataset, highlighting the need for continued investigation.

The divergent expression and functional relationships between MLH1 and GPRC5C illuminate a complex regulatory axis that may govern tumor aggressiveness in hepatocellular carcinoma. MLH1, traditionally implicated in maintaining genomic integrity through mismatch repair, appears to confer tumor-suppressive effects. Its loss may unleash oncogenic pathways, partially mediated by increased GPRC5C activity, which promotes tumor growth and invasion.

From a translational perspective, these findings open avenues for developing MLH1 and GPRC5C as biomarkers for risk stratification in HCC patients. Evaluating their expression could help identify individuals who are more likely to benefit from surgical resection or require more intensive follow-up and adjuvant therapies. Furthermore, targeting the GPRC5C pathway might emerge as an innovative therapeutic strategy to curb tumor progression.

The study also emphasizes the utility of tissue microarray platforms combined with immunohistochemistry to unravel complex molecular signatures in cancer specimens. This approach enables high-throughput, standardized assessment across large patient cohorts, bolstering the reproducibility and clinical relevance of biomarker studies.

While the current results are promising, the authors caution that further functional studies and clinical trials are essential to clarify the mechanistic underpinnings of MLH1-GPRC5C interplay in hepatocellular carcinoma. Understanding how these proteins influence signaling cascades, cellular proliferation, and metastatic potential will be pivotal for translating these molecular insights into effective treatments.

In summary, Lu and colleagues present compelling evidence that MLH1 and GPRC5C serve as potent, inversely correlated prognostic markers in resectable hepatocellular carcinoma. Their work offers a nuanced perspective on liver cancer pathology, underscoring the interplay between DNA repair deficiency and G-protein coupled receptor signaling in dictating tumor behavior.

As hepatocellular carcinoma incidence continues to rise globally, driven by factors such as chronic hepatitis infections and metabolic disorders, the need for precise biomarkers and targeted interventions intensifies. Investigations like this one provide critical stepping stones toward personalized oncology, wherein molecular profiling of tumors guides therapeutic decision-making and ultimately improves patient survival.

Future research should explore how modulation of MLH1 and GPRC5C expression affects tumor microenvironment interactions, immune evasion, and response to emerging therapies such as immune checkpoint inhibitors and targeted agents. Integrating these molecular biomarkers with clinical parameters promises to refine existing staging systems and optimize management of hepatocellular carcinoma.

This landmark study thus marks a significant advance in the cancer biomarker field and highlights the dynamic interplay between DNA repair processes and receptor-mediated signaling in the pathogenesis and progression of hepatocellular carcinoma.

Subject of Research: Expression patterns and prognostic significance of MLH1 and GPRC5C in resectable hepatocellular carcinoma.

Article Title: Expression and prognostic significance of MLH1 and GPRC5C in resectable hepatocellular carcinoma

Article References:
Lu, J., Li, L., Chen, Q. et al. Expression and prognostic significance of MLH1 and GPRC5C in resectable hepatocellular carcinoma. BMC Cancer 25, 1215 (2025). https://doi.org/10.1186/s12885-025-14591-1

Image Credits: Scienmag.com

DOI: https://doi.org/10.1186/s12885-025-14591-1

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