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Myoferlin regulates epithelial cancer cell plasticity and migration through autocrine TGF-?1 signaling.


ABSTRACT: Epithelial cancer cells can undergo an epithelial-mesenchymal transition (EMT), a complex genetic program that enables cells to break free from the primary tumor, breach the basement membrane, invade through the stroma and metastasize to distant organs. Myoferlin (MYOF), a protein involved in plasma membrane function and repair, is overexpressed in several invasive cancer cell lines. Depletion of myoferlin in the human breast cancer cell line MDA-MB-231 (MDA-231MYOFKD) reduced migration and invasion and caused the cells to revert to an epithelial phenotype. To test if this mesenchymal-epithelial transition was durable, MDA-231MYOFKD cells were treated with TGF-?1, a potent stimulus of EMT. After 48 hr with TGF-?1, MDA-231MYOFKD cells underwent an EMT. TGF-?1 treatment also decreased directional cell motility toward more random migration, similar to the highly invasive control cells. To probe the potential mechanism of MYOF function, we examined TGF-?1 receptor signaling. MDA-MB-231 growth and survival has been previously shown to be regulated by autocrine TGF-?1. We hypothesized that MYOF depletion may result in the dysregulation of TGF-?1 signaling, thwarting EMT. To investigate this hypothesis, we examined production of endogenous TGF-?1 and observed a decrease in TGF-?1 protein secretion and mRNA transcription. To determine if TGF-?1 was required to maintain the mesenchymal phenotype, TGF-? receptor signaling was inhibited with a small molecule inhibitor, resulting in decreased expression of several mesenchymal markers. These results identify a novel pathway in the regulation of autocrine TGF-? signaling and a mechanism by which MYOF regulates cellular phenotype and invasive capacity of human breast cancer cells.

SUBMITTER: Barnhouse VR 

PROVIDER: S-EPMC5922389 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Myoferlin regulates epithelial cancer cell plasticity and migration through autocrine TGF-β1 signaling.

Barnhouse Victoria R VR   Weist Jessica L JL   Shukla Vasudha C VC   Ghadiali Samir N SN   Kniss Douglas A DA   Leight Jennifer L JL  

Oncotarget 20180410 27


Epithelial cancer cells can undergo an epithelial-mesenchymal transition (EMT), a complex genetic program that enables cells to break free from the primary tumor, breach the basement membrane, invade through the stroma and metastasize to distant organs. Myoferlin (MYOF), a protein involved in plasma membrane function and repair, is overexpressed in several invasive cancer cell lines. Depletion of myoferlin in the human breast cancer cell line MDA-MB-231 (MDA-231<sup>MYOFKD</sup>) reduced migrati  ...[more]

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