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Research Paper|Volume 16, Issue 2|pp 1620—1639

PROX1 interaction with α-SMA-rich cancer-associated fibroblasts facilitates colorectal cancer progression and correlates with poor clinical outcomes and therapeutic resistance

Shiue-Wei Lai1, Yi-Chiao Cheng2, Kee-Thai Kiu3,4, Min-Hsuan Yen3,4, Ying-Wei Chen3,4, Vijesh Kumar Yadav5,6, Chi-Tai Yeh5,6,7, Kuang-Tai Kuo8,9, Tung-Cheng Chang3,4
  • 1Department of Internal Medicine, Division of Hematology and Oncology, Tri-service General Hospital, National Defense Medical Center, Taipei, Taiwan
  • 2Department of Surgery, Division of Colon and Rectal Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
  • 3Department of Surgery, Division of Colorectal Surgery, Taipei Medical University Shuang-Ho Hospital, Taipei, Taiwan
  • 4Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
  • 5Department of Internal Medicine, Division of Gastroenterology and Hepatology, Shuang-Ho Hospital, New Taipei City, Taiwan
  • 6Department of Medical Research and Education, Taipei Medical University Shuang-Ho Hospital, New Taipei City 23561, Taiwan
  • 7Continuing Education Program of Food Biotechnology Applications, College of Science and Engineering, National Taitung University, Taitung 95092, Taiwan
  • 8Department of Surgery, Division of Thoracic Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
  • 9Department of Surgery, Division of Thoracic Surgery, Taipei Medical University Shuang-Ho Hospital, New Taipei City 23561, Taiwan
Received: May 16, 2023Accepted: November 30, 2023Published: January 18, 2024
https://doi.org/10.18632/aging.205447

Copyright: © 2024 Lai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Background: The tumor microenvironment (TME) plays a vital role in tumor progression through intricate molecular interactions. Cancer-associated fibroblasts (CAFs), notably those expressing alpha-smooth muscle actin (α-SMA) or myofibroblasts, are instrumental in this context and correlate with unfavorable outcomes in colorectal cancer (CRC). While several transcription factors influence TME, the exact regulator causing CAF dysregulation in CRC remains elusive. Prospero Homeobox 1 (PROX1) stands out, as its inhibition reduces α-SMA-rich CAF activity. However, the therapeutic role of PROX1 is debated due to inconsistent study findings.

Methods: Using the ULCAN portal, we noted an elevated PROX1 level in advanced colon adenocarcinoma, linking to a poor prognosis. Assays determined the impact of PROX1 overexpression on CRC cell properties, while co-culture experiments spotlighted the PROX1-CAF relationship. Molecular expressions were validated by qRT-PCR and Western blots, with in vivo studies further solidifying the observations.

Results: Our study emphasized the connection between PROX1 and α-SMA in CAFs. Elevated PROX1 in CRC samples correlated with increased α-SMA in tumors. PROX1 modulation influenced the behavior of specific CRC cells, with its overexpression fostering invasiveness. Kaplan-Meier evaluations demonstrated a link between PROX1 or α-SMA and survival outcomes. Consequently, PROX1, alone or with α-SMA, emerges as a CRC prognostic marker. Co-culture and animal experiments further highlighted this relationship.

Conclusion: PROX1 appears crucial in modulating CRC behavior and therapeutic resistance within the TME by influencing CAFs, signifying the combined PROX1/α-SMA gene as a potential CRC prognostic marker. The concept of developing inhibitors targeting this gene set emerges as a prospective therapeutic strategy. However, this study is bound by limitations, including potential challenges in clinical translation, a focused exploration on PROX1/α-SMA potentially overlooking other significant molecular contributors, and the preliminary nature of the inhibitor development proposition.