Targeting MACC1 Offers Promising Therapeutic Strategy for PAH

Through the integration of a variety of bioinformatic approaches, metastasis-associated in colon cancer 1 (MACC1) has emerged as a promising biomarker that can be used to better diagnosis and treat pulmonary arterial hypertension (PAH), shedding light on the mechanisms of PAH development at the protein and transcriptome levels, according to a study published in Computers in Biology and Medicine.

Vasodilators have been the standard of PAH treatment for some time, yet they have been insufficient in reversing the excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) that drive PAH. Therefore, discovering new pathobiological mechanisms to develop novel therapeutic targets to address underlying pathological remodeling is essential.

MACC1 has been found in xenografted, patient-derived, and transgenic mouse models to induce tumor initiation, progression, and liver and lung metastasis. Previous research shows it to be a reliable predictive marker for lung cancer, although MACC1’s role in treating PAH has remained unclear.

In their study, the investigators pooled data from 2 gene sets for analysis: GSE113439 and GSE117261. In total, 201 differentially expressed genes (DEGs) were discovered, with 157 genes being upregulated and 44 genes being downregulated.

Previous research shows MACC1 to be a reliable predictive marker for lung cancer, but a role in treating PAH remains unclear | Image Credit: Orawan-stock.adobe.com

Further validation analysis in a separate gene set—GSE22356—indicates that MACC1 consistently exhibits upregulation in the serum of patients who have PAH, the investigators found. Blood samples from 59 patients with PAH and 22 healthy individuals were collected to determine serum MACC1 levels, with results showing that serum MACC1 levels were higher in patients compared with the healthy controls.

Additionally, MACC1 expression was verified by the investigators using lung homogenate from MCT-or hypoxia-treated rats. These Western blot analyses revealed a significant upregulation of MACC1 vs controls, the investigators observed.

To provide additional clarification on the role of MACC1 in PASMCs, the biomarker was knocked down at the transcriptional level for to see if decreasing MACC1 levels improves the malignant phenotypes of PASMCs. This knockdown resulted in the downregulation of platelet-derived growth factor (PDGF)-induced proliferating cell nuclear antigen expression, a proliferation marker, while exacerbating the expression of BAX/Bcl-2, which are apoptosis markers.

These results suggest a pivotal role for MACC1 in PDGF BB (PDGF-BB)-induced proliferation and resistance to apoptosis in PASMCs, the investigators discussed. Using a wound healing assay, they predicted whether MACC1 is an essential factor for PDGF-BB–induced PASMC migration; this revealed a significant increase in migratory PASMCs upon the interference of MACC1, according to the investigators.

They then discussed the increasing prevalence of research attempting to explore the underlying pathogenesis of PH through bioinformatic analysis but acknowledged that this approach could introduce bias and identify DEGs that don’t have any biological relevance. The integrated bioinformatics analysis conducted in the current study revealed 4 significant hub genes: ANKRD36C, COL14A1, POSTN, and MACC1.

For the first time, serum MACC1 levels were revealed to be higher in patients who have PAH than in healthy controls and was found to be positively correlated with World Health Organization cardiac function class, suggesting the potential for using MACC1 as a diagnostic marker for PAH, the investigators wrote. Despite these advancements, the true potential therapeutic value of MACC1 necessitates further attention.

“Overall, the integration of various bioinformatic approaches has culminated in the identification of 4 key genes in PAH, with MACC1 emerging as a promising biomarker for early diagnosis and treatment of the disease… However, further investigations are warranted to validate our findings and ascertain the therapeutic potential of MACC1 as a therapeutic target for PAH intervention,” the study authors concluded.

Reference

Zhou X, Liang B, Lin W, et al. Identification of MACC1 as a potential biomarker for pulmonary arterial hypertension based on bioinformatics and machine learning. Comput Biol Med. 2024;173:108372. doi:10.1016/j.compbiomed.2024.108372