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Int J Biol Sci 2024; 20(1):265-279. doi:10.7150/ijbs.86275 This issue Cite

Research Paper

EXOSC5 maintains cancer stem cell activity in endometrial cancer by regulating the NTN4/integrin β1 signalling axis

Yu-Hao Huang^1,2, Wen-Ling Wang², Po-Hui Wang^3,4,5, Hsueh-Te Lee^1,6,7,8✉, Wen-Wei Chang^2,9✉

1. Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 112304, Taiwan.
2. Department of Biomedical Sciences, Chung Shan Medical University, Taichung 402306, Taiwan.
3. Institute of Medicine, Chung Shan Medical University, Taichung 402306, Taiwan.
4. Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung 402306, Taiwan.
5. School of Medicine, Chung Shan Medical University, Taichung 402306, Taiwan.
6. Institute of Anatomy & Cell Biology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan.
7. Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 115024, Taiwan.
8. Brain Research Center, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan.
9. Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402306, Taiwan.

✉ Corresponding authors: changwwedu.tw (W.-W.C.); incubator.leeedu.tw (H.-T.L.); Tel.: +886-4-2473-0022 (ext. 12305) (W.-W.C.); +886-2-28267073 (H.-T.L.); Fax: +886-2-2821-2884 (H.-T.L.).

Abstract

Endometrial carcinoma (EC) is a common type of uterine cancer in developed countries, originating from the uterine epithelium. The incidence rate of EC in Taiwan has doubled from 2005. Cancer stem cells (CSCs) are a subpopulation of cancer cells that have high tumorigenicity and play a crucial role in the malignant processes of cancer. Targeting molecules associated with CSCs is essential for effective cancer treatments. This study delves into the role of Exosome component 5 (EXOSC5) in EC. Data from The Cancer Genome Atlas suggests a correlation between high EXOSC5 mRNA expression and unfavorable EC prognosis. EXOSC5 knockdown diminished EC-CSC self-renewal and reduced expression of key cancer stemness proteins, including c-MYC and SOX2. Intriguingly, this knockdown significantly curtailed tumorigenicity and CSC frequency in EC tumor spheres. A mechanistic examination revealed a reduction in netrin4 (NTN4) levels in EXOSC5-depleted EC cells. Moreover, NTN4 treatment amplified EC cell CSC activity and, when secreted, NTN4 partnered with integrin β1, subsequently triggering the FAK/SRC axis to elevate c-MYC activity. A clear positive relation between EXOSC5 and NTN4 was evident in 93 EC tissues. In conclusion, EXOSC5 augments NTN4 expression, activating c-MYC via the integrin β1/FAK/SRC pathway, offering potential avenues for EC diagnosis and treatment.

Keywords: Endometrial carcinoma, cancer stem cells, c-MYC, EXOSC5, NTN4, integrin β1

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