DEPTOR induces a partial epithelial-to-mesenchymal transition and metastasis via autocrine TGFβ1 signaling and is associated with poor prognosis in hepatocellular carcinoma

Abstract

Background DEPTOR is an endogenous inhibitor of mTORC1 and mTORC2 that plays a vital role in the progression of human malignances. However, the biological function of DEPTOR in HCC metastasis and the underlying molecular mechanisms are still unclear. Methods Western blot analysis and immunohistochemistry(IHC) were employed to examine DEPTOR expression in HCC cell lines and tissues. A series of in vivo and in vitro assays were performed to determine the function of DEPTOR and the possible mechanisms underlying its role in HCC metastasis. Results We found that DEPTOR was frequently overexpressed in HCC tissues, and its high expression was associated with high serum AFP levels, increased tumor size, vascular invasion and more advanced TMN and BCLC stage, as well as an overall poor prognosis. Functional experiments demonstrated that DEPTOR silencing inhibited the proliferation and mobility of HCC cells in vitro and suppressed tumor growth and metastasis of HCC cells in vivo. Accordingly, DEPTOR overexpression promoted the invasion and metastasis of HCC cells in vitro and in vivo, but had no effect on cell proliferation in vitro. Overexpression of DEPTOR induced EMT by snail induction. Conversely, knockdown of snail expression impaired the DEPTOR-induced migration, invasion and EMT of HCC cells. Furthermore, we found that the increase of snail expression by DEPTOR overexpression was due to an activation of TGF-β1-smad3/smad4 signaling possibly through feedback inhibition of mTOR. Conclusion DEPTOR promotes the EMT and metastasis of HCC cells by activating the TGF-β1-smad3/smad4-snail pathway via mTOR inhibition. Therefore, targeting DEPTOR may be an ideal treatment strategy for inhibiting the growth and metastasis of HCC. Electronic supplementary material The online version of this article (10.1186/s13046-019-1220-1) contains supplementary material, which is available to authorized users.

Emerging Concepts of Hybrid Epithelial-to-Mesenchymal Transition in Cancer Progression

“…Overexpression of DEPTOR promotes proliferation and survival of cancer cells. DEPTOR induces a partial E-to-M transition and metastasis via autocrine TGF-β1 signaling in HCC [27]. Endosulfan is an organochlorine pesticide that is mainly metabolised by cytochrome P450 (CYP) enzymes, CYT2B6 and CYT3A4, in human liver.…”

Unresolved Complexity in the Gene Regulatory Network Underlying EMT

“…Unraveling inter-pathway regulation in EMT and deciphering what signaling pathways are required for different stages/steps of EMT (e.g., initiation, progression, maintenance, the cadherin switch, loss of cell polarity and other phenotypic alterations) is of vital importance. Recently, the DEPTOR (DEP domain containing mTOR interacting) protein which normally inhibits mTOR signaling, stimulated partial EMT in HCC cells by activating TGFβ-Smad3/4-Snail signaling through mTOR inhibition (88). Similarly, in vitro mimicking of ECM organization showed that the way the ECM is arranged could trigger partial or full EMT (89).…”

Autocrine TGF-β in Cancer: Review of the Literature and Caveats in Experimental Analysis

“…Lastly, overexpression of DEPTOR, an mTOR-interacting protein, whose expression is negatively regulated by mTORC1 and mTORC2, promoted the invasion and metastasis of HCC cells in vitro and in vivo. DEPTOR induced an EMT and metastasis via up-regulation of Snail, which was due, in turn, to activation of aTGF-β1-Smad3/4 signaling, possibly through feedback inhibition of mTOR [ 82 ].…”