PMID- 38244581 OWN - NLM STAT- MEDLINE DCOM- 20240206 LR - 20240216 IS - 1945-4589 (Electronic) IS - 1945-4589 (Linking) VI - 16 IP - 2 DP - 2024 Jan 18 TI - PROX1 interaction with alpha-SMA-rich cancer-associated fibroblasts facilitates colorectal cancer progression and correlates with poor clinical outcomes and therapeutic resistance. PG - 1620-1639 LID - 10.18632/aging.205447 [doi] AB - 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 (alpha-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 alpha-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 alpha-SMA in CAFs. Elevated PROX1 in CRC samples correlated with increased alpha-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 alpha-SMA and survival outcomes. Consequently, PROX1, alone or with alpha-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/alpha-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/alpha-SMA potentially overlooking other significant molecular contributors, and the preliminary nature of the inhibitor development proposition. FAU - Lai, Shiue-Wei AU - Lai SW AD - Department of Internal Medicine, Division of Hematology and Oncology, Tri-service General Hospital, National Defense Medical Center, Taipei, Taiwan. FAU - Cheng, Yi-Chiao AU - Cheng YC AD - Department of Surgery, Division of Colon and Rectal Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. FAU - Kiu, Kee-Thai AU - Kiu KT AD - Department of Surgery, Division of Colorectal Surgery, Taipei Medical University Shuang-Ho Hospital, Taipei, Taiwan. AD - Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. FAU - Yen, Min-Hsuan AU - Yen MH AD - Department of Surgery, Division of Colorectal Surgery, Taipei Medical University Shuang-Ho Hospital, Taipei, Taiwan. AD - Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. FAU - Chen, Ying-Wei AU - Chen YW AD - Department of Surgery, Division of Colorectal Surgery, Taipei Medical University Shuang-Ho Hospital, Taipei, Taiwan. AD - Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. FAU - Yadav, Vijesh Kumar AU - Yadav VK AD - Department of Internal Medicine, Division of Gastroenterology and Hepatology, Shuang-Ho Hospital, New Taipei City, Taiwan. AD - Department of Medical Research and Education, Taipei Medical University Shuang-Ho Hospital, New Taipei City 23561, Taiwan. FAU - Yeh, Chi-Tai AU - Yeh CT AD - Department of Internal Medicine, Division of Gastroenterology and Hepatology, Shuang-Ho Hospital, New Taipei City, Taiwan. AD - Department of Medical Research and Education, Taipei Medical University Shuang-Ho Hospital, New Taipei City 23561, Taiwan. AD - Continuing Education Program of Food Biotechnology Applications, College of Science and Engineering, National Taitung University, Taitung 95092, Taiwan. FAU - Kuo, Kuang-Tai AU - Kuo KT AD - Department of Surgery, Division of Thoracic Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. AD - Department of Surgery, Division of Thoracic Surgery, Taipei Medical University Shuang-Ho Hospital, New Taipei City 23561, Taiwan. FAU - Chang, Tung-Cheng AU - Chang TC AD - Department of Surgery, Division of Colorectal Surgery, Taipei Medical University Shuang-Ho Hospital, Taipei, Taiwan. AD - Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. LA - eng PT - Journal Article DEP - 20240118 PL - United States TA - Aging (Albany NY) JT - Aging JID - 101508617 RN - 0 (Actins) SB - IM MH - Animals MH - *Cancer-Associated Fibroblasts/metabolism MH - Actins/metabolism MH - *Colonic Neoplasms/genetics MH - Genes, Homeobox MH - *Adenocarcinoma/genetics MH - Drug Resistance, Neoplasm MH - *Colorectal Neoplasms/drug therapy/genetics/metabolism MH - Tumor Microenvironment/genetics MH - Fibroblasts/metabolism PMC - PMC10866434 OTO - NOTNLM OT - PROX1 OT - biomarker OT - cancer-associated fibroblast OT - colorectal cancer OT - metastasis OT - prognosis OT - alpha-SMA COIS- CONFLICTS OF INTEREST: The authors declare no conflicts of interest related to this study. EDAT- 2024/01/21 00:42 MHDA- 2024/02/06 06:42 PMCR- 2024/01/31 CRDT- 2024/01/20 19:02 PHST- 2023/05/16 00:00 [received] PHST- 2023/11/30 00:00 [accepted] PHST- 2024/02/06 06:42 [medline] PHST- 2024/01/21 00:42 [pubmed] PHST- 2024/01/20 19:02 [entrez] PHST- 2024/01/31 00:00 [pmc-release] AID - 205447 [pii] AID - 10.18632/aging.205447 [doi] PST - ppublish SO - Aging (Albany NY). 2024 Jan 18;16(2):1620-1639. doi: 10.18632/aging.205447. Epub 2024 Jan 18.