4.7 Article

CAF-derived exosomal WEE2-AS1 facilitates colorectal cancer progression via promoting degradation of MOB1A to inhibit the Hippo pathway

Journal

CELL DEATH & DISEASE
Volume 13, Issue 9, Pages -

Publisher

SPRINGERNATURE
DOI: 10.1038/s41419-022-05240-7

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Funding

  1. Primary Research & Development Plan of Jiangsu Province [BE2021742]
  2. Jiangsu Provincial Natural Science Foundation for Basic Research, China [BK20201491]
  3. National Key R&D Program of China [2017YFC0908200]
  4. Jiangsu Key Medical Discipline (General Surgery) [ZDxKA2016005]

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In this study, it was found that WEE2-AS1 is highly expressed in CAF-derived sEVs in the tumor microenvironment. The level of WEE2-AS1 is elevated in plasma sEVs of CRC patients, which is associated with advanced pathological staging and poor survival. Functional experiments revealed that elevated expression of WEE2-AS1 in sEVs increases CRC cell proliferation and promotes tumor formation and progression. Mechanistically, WEE2-AS1 interacts with MOB1A, inhibits the Hippo pathway, and facilitates the growth of CRC cells.
Cancer-associated fibroblasts (CAFs) are the most abundant stromal components in the tumor microenvironment (TME) and closely involved in tumor progression. However, the precise biological functions and molecular mechanisms of CAFs in the TME have yet to be understood. Here, we demonstrate that WEE2-AS1 is highly expressed in the CAF-derived small extracellular vesicles (sEVs). Moreover, WEE2-AS1 is markedly higher in plasma sEVs of CRC patients than in healthy subjects and its high level predicts advanced pathological staging and poor survival. Then, we conducted a series of in vitro and in vivo experiments. Elevated expression of WEE2-AS1 in sEVs increases CRC cell proliferation in vitro. Importantly, aberrant CAF-sEVs(WEE2-AS1) leads to tumor formation and progression in BALB/c nude mice and promotes AOM/DSS-induced tumorigenesis. Mechanistically, WEE2-AS1 functions as a modular scaffold for the MOB1A and E3 ubiquitin-protein ligase praja2 complexes, leading to MOB1A degradation via the ubiquitin-proteasome pathway. The Hippo pathway is then inhibited and more YAP are transported into the nucleus, where they activate downstream gene transcription. Together, our data reveal that CAF-sEVs(WEE2-AS1) interacts with MOB1A, promotes degradation of MOB1A, inhibits the Hippo pathway, and facilitates the growth of CRC cells. Hence, exosomal WEE2-AS1 may be a promising therapeutic target and circulating biomarker for CRC diagnosis and prognosis.

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