Secretory Lysosome-Related Gene Signature Defines the Immune Microenvironment and Identifies RGS2 as a Prometastatic...

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Hepatocellular carcinoma (HCC) is aggressive with poor immunotherapy response.
• Secretory lysosomes (SLs) influence immune responses, but their role in HCC is unclear.
• Investigating secretory lysosome-related genes (SLRGs) is crucial for HCC prognosis.

Purpose of the Study:

• To develop a predictive signature for HCC prognosis using immune lysosome-related genes (immLysorgs).
• To evaluate the functional role of RGS2 in HCC progression and its potential as a therapeutic target.

Main Methods:

• Identified 13 immLysorgs and analyzed TCGA-LIHC and GSE76427 cohort data.
• Utilized non-negative matrix factorization and consensus clustering for molecular subtyping.
• Developed a predictive model (immLysoS) using LASSO and Cox regression, including GZMH, KLRB1, RGS2, and SLC6A1, and validated it across cohorts. Functional studies assessed RGS2's role.

Main Results:

• Discovered two subtypes (C1/C2) and two genotypes (A/B), with C2/A showing better survival and immune infiltration.
• The immLysoS signature effectively stratified patients into risk groups with distinct survival outcomes.
• High immLysoS scores correlated with advanced HCC, higher grade, and specific mutations (TP53, CTNNB1). Low-risk patients showed better response to PD-L1 inhibitors and sorafenib.
• RGS2 knockdown inhibited HCC cell proliferation, migration, and tumor growth in vitro and in vivo.

Conclusions:

• The immLysoS signature is a valuable tool for HCC risk assessment and personalized therapy recommendations.
• It links SL-related genes to immune characteristics and treatment response in HCC.
• RGS2 is identified as a potential oncogenic driver and therapeutic target in HCC, warranting further investigation.