A recent research paper published in the journal Aging has revealed a significant correlation between PROX1 and α-SMA with colorectal cancer (CRC) progression, poor clinical outcomes, and resistance to therapy. The tumor microenvironment (TME) plays a crucial role in tumor progression, and cancer-associated fibroblasts (CAFs) expressing α-SMA have been identified as key players in this process and have been associated with unfavorable outcomes in CRC.
The exact regulator causing CAF dysregulation in CRC has remained unknown, despite the influence of several transcription factors on the TME. However, Prospero Homeobox 1 (PROX1) has emerged as a potential candidate, as its inhibition has been shown to reduce the activity of α-SMA-rich CAFs. Nevertheless, the therapeutic role of PROX1 in CRC has been debated due to inconsistent study findings.
To shed light on this issue, a team of researchers from Taipei’s National Defense Medical Center, Taipei Medical University, Taipei Medical University Shuang-Ho Hospital, and National Taitung University conducted a study using the ULCAN portal. They observed an elevated level of PROX1 in advanced colon adenocarcinoma, which was associated with a poor prognosis. The researchers conducted assays to determine the impact of PROX1 overexpression on CRC cell properties, and co-culture experiments highlighted the relationship between PROX1 and CAFs. The molecular expressions were validated using qRT-PCR and Western blots, and in vivo studies further corroborated the findings.
The study found that elevated levels of PROX1 in CRC samples correlated with increased α-SMA in tumors. Modulation of PROX1 influenced the behavior of specific CRC cells, with overexpression promoting invasiveness. Kaplan-Meier evaluations demonstrated a significant link between PROX1 or α-SMA and survival outcomes. Consequently, PROX1, alone or in combination with α-SMA, emerges as a potential prognostic marker for CRC. Co-culture and animal experiments further supported this relationship.
These findings highlight the crucial role of PROX1 in modulating CRC behavior and therapeutic resistance within the TME by influencing CAFs. As a result, the PROX1/α-SMA gene combination holds promise as a prognostic marker for CRC. The concept of developing inhibitors targeting this specific gene set could potentially be a therapeutic strategy for CRC. However, the study is subject to limitations, including potential challenges in translating these findings into a clinical setting, a narrow focus on PROX1/α-SMA that may overlook other significant molecular contributors, and the preliminary nature of the proposed inhibitor development.
Moving forward, the researchers emphasize the importance of developing and clinically validating small-molecule inhibitors targeting the PROX1/α-SMA combination. This could pave the way for refining and optimizing therapeutic interventions for CRC.
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1. Source: Coherent Market Insights, Public sources, Desk research
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