Dataset Information

Type III Transforming Growth Factor-? Receptor RNA Interference Enhances Transforming Growth Factor ?3-Induced Chondrogenesis Signaling in Human Mesenchymal Stem Cells.

ABSTRACT: The type III transforming growth factor-? (TGF-?) receptor (T?RIII), a coreceptor of the TGF-? superfamily, is known to bind TGF-?s and regulate TGF-? signaling. However, the regulatory roles of T?RIII in TGF-?-induced mesenchymal stem cell (MSC) chondrogenesis have not been explored. The present study examined the effect of T?RIII RNA interference (RNAi) on TGF-?3-induced human MSC (hMSC) chondrogenesis and possible signal mechanisms. A lentiviral expression vector containing T?RIII small interfering RNA (siRNA) (SiT?RIII) or a control siRNA (SiNC) gene was constructed and infected into hMSCs. The cells were cultured in chondrogenic medium containing TGF-?3 or control medium. T?RIII RNAi significantly enhanced TGF-?3-induced chondrogenic differentiation of hMSCs, the ratio of type II (T?RII) to type I (T?RI) TGF-? receptors, and phosphorylation levels of Smad2/3 as compared with cells infected with SiNC. An inhibitor of the TGF-? signal, SB431542, not only inhibited T?RIII RNAi-stimulated TGF-?3-mediated Smad2/3 phosphorylation but also inhibited the effects of T?RIII RNAi on TGF-?3-induced chondrogenic differentiation. These results demonstrate that T?RIII RNAi enhances TGF-?3-induced chondrogenic differentiation in hMSCs by activating TGF-?/Smad2/3 signaling. The finding points to the possibility of modifying MSCs by T?RIII knockdown as a potent future strategy for cell-based cartilage tissue engineering.

SUBMITTER: Zheng S

PROVIDER: S-EPMC6109468 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Type III Transforming Growth Factor-β Receptor RNA Interference Enhances Transforming Growth Factor β3-Induced Chondrogenesis Signaling in Human Mesenchymal Stem Cells.

Zheng Shuhui S Zhou Hang H Chen Zhuohui Z Li Yongyong Y Zhou Taifeng T Lian Chengjie C Lian Chengjie C Gao Bo B Su Peiqiang P Xu Caixia C

Stem cells international 20180808

The type III transforming growth factor-β (TGF-β) receptor (TβRIII), a coreceptor of the TGF-β superfamily, is known to bind TGF-βs and regulate TGF-β signaling. However, the regulatory roles of TβRIII in TGF-β-induced mesenchymal stem cell (MSC) chondrogenesis have not been explored. The present study examined the effect of TβRIII RNA interference (RNAi) on TGF-β3-induced human MSC (hMSC) chondrogenesis and possible signal me ...[more]

PMID: 30158983

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Project description:There is a major need to better understand the molecular basis of triple negative breast cancer (TNBC) in order to develop effective therapeutic strategies. Using gene expression data from 587 TNBC patients we previously identified six subtypes of the disease, among which a mesenchymal-stem like (MSL) subtype. The MSL subtype has significantly higher expression of the transforming growth factor beta (TGF-?) pathway-associated genes relative to other subtypes, including the TGF-? receptor type III (T?RIII). We hypothesize that T?RIII is tumor promoter in mesenchymal-stem like TNBC cells.Representative MSL cell lines SUM159, MDA-MB-231 and MDA-MB-157 were used to study the roles of T?RIII in the MSL subtype. We stably expressed short hairpin RNAs specific to T?RIII (T?RIII-KD). These cells were then used for xenograft tumor studies in vivo; and migration, invasion, proliferation and three dimensional culture studies in vitro. Furthermore, we utilized human gene expression datasets to examine T?RIII expression patterns across all TNBC subtypes.T?RIII was the most differentially expressed TGF-? signaling gene in the MSL subtype. Silencing T?RIII expression in MSL cell lines significantly decreased cell motility and invasion. In addition, when T?RIII-KD cells were grown in a three dimensional (3D) culture system or nude mice, there was a loss of invasive protrusions and a significant decrease in xenograft tumor growth, respectively. In pursuit of the mechanistic underpinnings for the observed T?RIII-dependent phenotypes, we discovered that integrin-?2 was expressed at higher level in MSL cells after T?RIII-KD. Stable knockdown of integrin-?2 in T?RIII-KD MSL cells rescued the ability of the MSL cells to migrate and invade at the same level as MSL control cells.We have found that T?RIII is required for migration and invasion in vitro and xenograft growth in vivo. We also show that T?RIII-KD elevates expression of integrin-?2, which is required for the reduced migration and invasion, as determined by siRNA knockdown studies of both T?RIII and integrin-?2. Overall, our results indicate a potential mechanism in which T?RIII modulates integrin-?2 expression to effect MSL cell migration, invasion, and tumorigenicity.

Dataset Information

Type III Transforming Growth Factor-? Receptor RNA Interference Enhances Transforming Growth Factor ?3-Induced Chondrogenesis Signaling in Human Mesenchymal Stem Cells.

Publications

Type III Transforming Growth Factor-<i>β</i> Receptor RNA Interference Enhances Transforming Growth Factor <i>β</i>3-Induced Chondrogenesis Signaling in Human Mesenchymal Stem Cells.

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