Combining TGF-β1 knockdown and miR200c administration to optimize antitumor efficacy of B16F10/GPI-IL-21 vaccine

Abstract

TGF-β1 secreted abundantly by tumors cells as well as present in the local microenvironment promotes neoplasm invasion and metastasis by triggering the epithelial to mesenchymal transition (EMT). MiR200c has been shown to suppress EMT and to regulate the cellular epithelial and interstitial state conversion, whereas the tumor vaccines are intended to specifically initiate or amplify a host response against evolving tumor cells. Our study aimed at optimizing the antitumor effects of the B16F10/glycosylphosphatidylinositol-interleukin 21 (B16F10/GPI-IL-21) tumor vaccine on melanoma bearing mice by combining the TGF-β1 knockdown and the administration of miR200c agomir. The mice were subcutaneously vaccinated with inactivated B16F10/GPI-IL-21 vaccine and challenged by B16F10 cells transfected with shTGF-β1 (B16F10/shTGF-β1 cells) or B16F10/shTGF-β1 cells with the administration of miR200c agomir. The later combination showed that, when compared with the mice in the control group that received no vaccination, vaccinated mice significantly increased NK and CTL activities, enhanced levels of IFN-γ, and reduced expression of TGF-β1, N-cadherin, Vimentin, Gli1/2, P-Smad2/3 and others involved in promoting expression of EMT-related molecules in tumor areas, and inhibited the melanoma metastasis in lungs and lymph nodes. Altogether, our findings demonstrate that this synergistic anti-cancer regimen effectively induces strong immune response and diminishes the melanoma progression.

Effect of targeted ovarian cancer immunotherapy using ovarian cancer stem cell vaccine

“…IFN-γ was generated by NK cells, while IFN-γ again reacted on NK cells, which may enhance cell-mediated cytotoxicity by delivering perforin and granzyme B, and develop central biological role in killing ovarian cancer cells [ 20 , 28 , 29 ]. Differently, the malignant tumors secreted the high amounts of TGF-β, which increased circulating plasma concentration that is associated with the advanced stage of the tumors [ 30 – 32 ]. The dysregulation of TGF-β signaling plays a crucial role in ovarian carcinogenesis and maintaining CSC properties [ 33 ].…”

miR‐200c regulates endothelin‐1 induced PASMCs abnormal proliferation and apoptosis

“…Zinc finger E‐box binding homeobox1 (ZEB‐1) is a transcription factor that plays crucial roles in the epithelial to mesenchymal transition of cancer cell . Most studies focused on miR‐200c regulation by the negative 3′‐UTR binding . Microtubule associated protein 2 (MAP‐2) as a member of the structural microtubule‐associated protein family which is mainly expressed in neuronal cells, epithelial tissues, and skeletal muscle.…”

Critical role of glioma‐associated oncogene homolog 1 in maintaining invasive and mesenchymal‐like properties of melanoma cells

“…The transcription factor glioma‐associated oncogene homolog 1 (GLI1) acts as a terminal, positive effector of Shh signaling, and Gli1 itself is a Shh‐target gene. GLI1's expression and activity are also regulated through a non‐canonical Shh pathway, such as those involving hypoxia or transforming growth factor (TGF)‐β . GLI1 has been suggested to be involved in melanoma progression, although its precise role and the mechanism underlying invasion remain unclear.…”