BMP2-induction of FN14 promotes protumorigenic signaling in gynecologic cancer cells

We previously reported that bone morphogenetic protein (BMP) signaling promotes tumorigenesis in gynecologic cancer cells. BMP2 enhances proliferation of ovarian and endometrial cancer cells via c-KIT induction, and triggers epithelial-mesenchymal transition (EMT) by SNAIL and/or SLUG induction, lea...

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Published in:Cellular signalling 2021-11, Vol.87, p.110146-110146, Article 110146
Main Authors: Fukuda, Tomohiko, Fukuda, Risa, Koinuma, Daizo, Moustakas, Aristidis, Miyazono, Kohei, Heldin, Carl-Henrik
Format: Article
Language:English
Subjects:
BMP
Bone Morphogenetic Protein 2 - pharmacology
c-KIT
Cell Line, Tumor
Cell Movement
Cell Proliferation
Endometrial cancer
Endometrial Neoplasms - genetics
Endometrial Neoplasms - pathology
Epithelial-Mesenchymal Transition
Female
FN14
Gene Knockdown Techniques
Gene Silencing
Humans
Ovarian cancer
Ovarian Neoplasms - genetics
Ovarian Neoplasms - pathology
Signal Transduction
SNAIL
TWEAK Receptor
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Summary:We previously reported that bone morphogenetic protein (BMP) signaling promotes tumorigenesis in gynecologic cancer cells. BMP2 enhances proliferation of ovarian and endometrial cancer cells via c-KIT induction, and triggers epithelial-mesenchymal transition (EMT) by SNAIL and/or SLUG induction, leading to increased cell migration. However, the downstream effectors of BMP signaling in gynecological cancer cells have not been clearly elucidated. In this study, we performed RNA-sequencing of Ishikawa endometrial and SKOV3 ovarian cancer cells after BMP2 stimulation, and identified TNFRSF12A, encoding fibroblast growth factor-inducible 14 (FN14) as a common BMP2-induced gene. FN14 knockdown suppressed BMP2-induced cell proliferation and migration, confirmed by MTS and scratch assays, respectively. In addition, FN14 silencing augmented chemosensitivity of SKOV3 cells. As a downstream effector of BMP signaling, FN14 modulated both c-KIT and SNAIL expression, which are important for growth and migration of ovarian and endometrial cancer cells. These results support the notion that the tumor promoting effects of BMP signaling in gynecological cancers are partially attributed to FN14 induction. •BMP2 induces FN14 in gynecologic cancer cells.•BMP2-induced FN14 enhances c-KIT expression and proliferation of ovarian cancer cells.•BMP2-induced FN14 increases SNAIL expression and migration of gynecologic cancer cells.
ISSN:0898-6568
1873-3913
1873-3913
DOI:10.1016/j.cellsig.2021.110146