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Mesenchymal stem cells promote colorectal cancer progression through AMPK/mTOR-mediated NF-κB activation.

Wu XB, Liu Y, Wang GH, Xu X, Cai Y, Wang HY, Li YQ, Meng HF, Dai F, Jin JD - Sci Rep (2016)

Bottom Line: This study was designed to identify the molecular mechanisms related to the tumor-promoting effect of MSCs in colorectal cancer.The tumorigenic effect of MSC-CM was attributed to altered expression of cell cycle regulatory proteins and inhibition of apoptosis.This study indicates that MSCs promote the progression of colorectal cancer via AMPK/mTOR-mediated NF-κB activation.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, the Third Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230061, P. R. China.

ABSTRACT
Mesenchymal stem cells (MSCs) exert a tumor-promoting effect in a variety of human cancers. This study was designed to identify the molecular mechanisms related to the tumor-promoting effect of MSCs in colorectal cancer. In vitro analysis of colorectal cancer cell lines cultured in MSC conditioned media (MSC-CM) showed that MSC-CM significantly promoted the progression of the cancer cells by enhancing cell proliferation, migration and colony formation. The tumorigenic effect of MSC-CM was attributed to altered expression of cell cycle regulatory proteins and inhibition of apoptosis. Furthermore, MSC-CM induced high level expression of a number of pluripotency factors in the cancer cells. ELISAs revealed MSC-CM contained higher levels of IL-6 and IL-8, which are associated with the progression of cancer. Moreover, MSC-CM downregulated AMPK mRNA and protein phosphorylation, but upregulated mTOR mRNA and protein phosphorylation. The NF-κB pathway was activated after addition of MSC-CM. An in vivo model in Balb/C mice confirmed the ability of MSC-CM to promote the invasion and proliferation of colorectal cancer cells. This study indicates that MSCs promote the progression of colorectal cancer via AMPK/mTOR-mediated NF-κB activation.

No MeSH data available.


Related in: MedlinePlus

Conditioned media from MSCs activates the NF-κB pathway in CRC cell lines.HCT116 cells were cultured in MSC-CM or control media for 24 h (A) Western blot analysis of P65 expression, P65 phosphorylation, IKBα expression and IKBα phosphorylation. (B) NF-KB activity was determined using an EMSA; Oct-1 severed as a control. (C) Quantification of P65 expression, P65 phosphorylation, IKBα expression and IKBα phosphorylation. *P  < 0.05 and **P < 0.01 vs. control group (n > 3).
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f6: Conditioned media from MSCs activates the NF-κB pathway in CRC cell lines.HCT116 cells were cultured in MSC-CM or control media for 24 h (A) Western blot analysis of P65 expression, P65 phosphorylation, IKBα expression and IKBα phosphorylation. (B) NF-KB activity was determined using an EMSA; Oct-1 severed as a control. (C) Quantification of P65 expression, P65 phosphorylation, IKBα expression and IKBα phosphorylation. *P  < 0.05 and **P < 0.01 vs. control group (n > 3).

Mentions: As described above, MSC-CM significantly increased the protein expression and phosphorylation of mTOR in HCT116 cells. The mTOR protein can affect the cell cycle, proliferation and differentiation by regulating a variety of cellular signals, including the NF-κB pathway. The NF-κB pathway contains several members, including the P65 subunit and its inhibitor IKBα. Western blotting demonstrated that culture in MSC-CM significantly increased the phosphorylation of P65 and IKBα in HCT116 cells (Fig. 6A,C) but did not alter the total expression of P65 (full-length blots are shown in Supplementary Figure S2.


Mesenchymal stem cells promote colorectal cancer progression through AMPK/mTOR-mediated NF-κB activation.

Wu XB, Liu Y, Wang GH, Xu X, Cai Y, Wang HY, Li YQ, Meng HF, Dai F, Jin JD - Sci Rep (2016)

Conditioned media from MSCs activates the NF-κB pathway in CRC cell lines.HCT116 cells were cultured in MSC-CM or control media for 24 h (A) Western blot analysis of P65 expression, P65 phosphorylation, IKBα expression and IKBα phosphorylation. (B) NF-KB activity was determined using an EMSA; Oct-1 severed as a control. (C) Quantification of P65 expression, P65 phosphorylation, IKBα expression and IKBα phosphorylation. *P  < 0.05 and **P < 0.01 vs. control group (n > 3).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4759824&req=5

f6: Conditioned media from MSCs activates the NF-κB pathway in CRC cell lines.HCT116 cells were cultured in MSC-CM or control media for 24 h (A) Western blot analysis of P65 expression, P65 phosphorylation, IKBα expression and IKBα phosphorylation. (B) NF-KB activity was determined using an EMSA; Oct-1 severed as a control. (C) Quantification of P65 expression, P65 phosphorylation, IKBα expression and IKBα phosphorylation. *P  < 0.05 and **P < 0.01 vs. control group (n > 3).
Mentions: As described above, MSC-CM significantly increased the protein expression and phosphorylation of mTOR in HCT116 cells. The mTOR protein can affect the cell cycle, proliferation and differentiation by regulating a variety of cellular signals, including the NF-κB pathway. The NF-κB pathway contains several members, including the P65 subunit and its inhibitor IKBα. Western blotting demonstrated that culture in MSC-CM significantly increased the phosphorylation of P65 and IKBα in HCT116 cells (Fig. 6A,C) but did not alter the total expression of P65 (full-length blots are shown in Supplementary Figure S2.

Bottom Line: This study was designed to identify the molecular mechanisms related to the tumor-promoting effect of MSCs in colorectal cancer.The tumorigenic effect of MSC-CM was attributed to altered expression of cell cycle regulatory proteins and inhibition of apoptosis.This study indicates that MSCs promote the progression of colorectal cancer via AMPK/mTOR-mediated NF-κB activation.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, the Third Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230061, P. R. China.

ABSTRACT
Mesenchymal stem cells (MSCs) exert a tumor-promoting effect in a variety of human cancers. This study was designed to identify the molecular mechanisms related to the tumor-promoting effect of MSCs in colorectal cancer. In vitro analysis of colorectal cancer cell lines cultured in MSC conditioned media (MSC-CM) showed that MSC-CM significantly promoted the progression of the cancer cells by enhancing cell proliferation, migration and colony formation. The tumorigenic effect of MSC-CM was attributed to altered expression of cell cycle regulatory proteins and inhibition of apoptosis. Furthermore, MSC-CM induced high level expression of a number of pluripotency factors in the cancer cells. ELISAs revealed MSC-CM contained higher levels of IL-6 and IL-8, which are associated with the progression of cancer. Moreover, MSC-CM downregulated AMPK mRNA and protein phosphorylation, but upregulated mTOR mRNA and protein phosphorylation. The NF-κB pathway was activated after addition of MSC-CM. An in vivo model in Balb/C mice confirmed the ability of MSC-CM to promote the invasion and proliferation of colorectal cancer cells. This study indicates that MSCs promote the progression of colorectal cancer via AMPK/mTOR-mediated NF-κB activation.

No MeSH data available.


Related in: MedlinePlus