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Enteric bacterial protein AvrA promotes colonic tumorigenesis and activates colonic beta-catenin signaling pathway.

Lu R, Wu S, Zhang YG, Xia Y, Liu X, Zheng Y, Chen H, Schaefer KL, Zhou Z, Bissonnette M, Li L, Sun J - Oncogenesis (2014)

Bottom Line: In the current study, we colonized mice with Salmonella AvrA-sufficient or AvrA-deficient Salmonella typhimirium strains and induced inflammation-associated colon cancer by azoxymethane/dextran sulfate sodium (AOM/DSS).Tumor incidence in the AvrA+infected group was 100% compared with 51.4% in the AOM/DSS group without bacterial gavage and 56.3% in mice infected with the AvrA- strain.Our observations also raise a note of caution regarding the use of mutant Salmonella organisms as vectors for anti-cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Rush University, Chicago, IL, USA.

ABSTRACT
Salmonella infections can become chronic and increase the risk of cancer. The mechanisms by which specific Salmonella organisms contribute to cancer, however, are still unknown. Live and attenuated Salmonella are used as vectors to target cancer cells, but there have been no systematic studies of the oncogenic potential of chronic Salmonella infections in cancer models. AvrA, a pathogenic product of Salmonella, is inserted into host cells during infection and influences eukaryotic cell pathways. In the current study, we colonized mice with Salmonella AvrA-sufficient or AvrA-deficient Salmonella typhimirium strains and induced inflammation-associated colon cancer by azoxymethane/dextran sulfate sodium (AOM/DSS). We confirmed Salmonella persisted in the colon for up to 45 weeks. Salmonella was identified not only in epithelial cells on the colonic luminal surface and base of the crypts but also in invading tumors. Tumor incidence in the AvrA+infected group was 100% compared with 51.4% in the AOM/DSS group without bacterial gavage and 56.3% in mice infected with the AvrA- strain. Infection with AvrA+ strain also altered tumor distribution from the distal to proximal colon that might reflect changes in the microbiome. AvrA-expressing bacteria also upregulated beta-catenin signaling as assessed by decreased beta-catenin ubiquitination, increased nuclear beta-catenin and increased phosphorylated-beta-catenin (Ser552), a marker of proliferating stem-progenitor cells. Other β-catenin targets increased by AvrA included Bmi1, a cancer stem cell marker, matrix metalloproteinase-7, and cyclin D1. In summary, AvrA-expressing Salmonella infection activates β-catenin signals and enhances colonic tumorigenesis. Our findings provide important new mechanistic insights into how a bacterial protein targets proliferating stem-progenitor cells and contributes to cancer development. Our observations also raise a note of caution regarding the use of mutant Salmonella organisms as vectors for anti-cancer therapy. Finally, these studies could suggest biomarkers (such as AvrA level in gut) to assess cancer risk in susceptible individuals and infection-related dysregulation of β-catenin signaling in cancer.

No MeSH data available.


Related in: MedlinePlus

AvrA regulates β-catenin activation as assessed by phospho (Ser552) β-catenin in AOM/DSS-induced tumors. (a) β-Catenin localization in control mucosa and colonic tumors. (b) P-β-catenin Ser552 localization in control mucosa and colonic tumors. (c) Quantitation of nuclear P-β-catenin Ser552 in control mucosa and colonic tumors. Data are means±s.d. of n=3 control mice or AOM/DSS tumors in each group. *P<0.05, **P<0.01 (d) Expression levels of p-β-catenin, total β-catenin and Akt and P-Akt as assessed by western blotting in control and AOM/DSS-induced tumors. Shown are control mucosa and tumors representative of three mice in each group. (e) Immunostaining of p-Myc, MMP-7, Cyclin D1 and Bmi1 in control colons and AOM/DSS-induced tumors (left panel). Quantitative imaging of nuclear Bmi1 in control mucosa and mucosa adjacent to tumors (right panel). Data are means±s.d. of n=3 control mice or AOM/DSS mice in each group. *P<0.05, **P<0.01.
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fig3: AvrA regulates β-catenin activation as assessed by phospho (Ser552) β-catenin in AOM/DSS-induced tumors. (a) β-Catenin localization in control mucosa and colonic tumors. (b) P-β-catenin Ser552 localization in control mucosa and colonic tumors. (c) Quantitation of nuclear P-β-catenin Ser552 in control mucosa and colonic tumors. Data are means±s.d. of n=3 control mice or AOM/DSS tumors in each group. *P<0.05, **P<0.01 (d) Expression levels of p-β-catenin, total β-catenin and Akt and P-Akt as assessed by western blotting in control and AOM/DSS-induced tumors. Shown are control mucosa and tumors representative of three mice in each group. (e) Immunostaining of p-Myc, MMP-7, Cyclin D1 and Bmi1 in control colons and AOM/DSS-induced tumors (left panel). Quantitative imaging of nuclear Bmi1 in control mucosa and mucosa adjacent to tumors (right panel). Data are means±s.d. of n=3 control mice or AOM/DSS mice in each group. *P<0.05, **P<0.01.

Mentions: It is known that β-catenin signaling is activated in colonic tumorigenesis.23 In agreement with previous studies, we observed that nuclear β-catenin was upregulated in AOM/DSS-induced tumors (Figure 3a). Nuclear localization suggested that β-catenin is also activated (Figure 3a).


Enteric bacterial protein AvrA promotes colonic tumorigenesis and activates colonic beta-catenin signaling pathway.

Lu R, Wu S, Zhang YG, Xia Y, Liu X, Zheng Y, Chen H, Schaefer KL, Zhou Z, Bissonnette M, Li L, Sun J - Oncogenesis (2014)

AvrA regulates β-catenin activation as assessed by phospho (Ser552) β-catenin in AOM/DSS-induced tumors. (a) β-Catenin localization in control mucosa and colonic tumors. (b) P-β-catenin Ser552 localization in control mucosa and colonic tumors. (c) Quantitation of nuclear P-β-catenin Ser552 in control mucosa and colonic tumors. Data are means±s.d. of n=3 control mice or AOM/DSS tumors in each group. *P<0.05, **P<0.01 (d) Expression levels of p-β-catenin, total β-catenin and Akt and P-Akt as assessed by western blotting in control and AOM/DSS-induced tumors. Shown are control mucosa and tumors representative of three mice in each group. (e) Immunostaining of p-Myc, MMP-7, Cyclin D1 and Bmi1 in control colons and AOM/DSS-induced tumors (left panel). Quantitative imaging of nuclear Bmi1 in control mucosa and mucosa adjacent to tumors (right panel). Data are means±s.d. of n=3 control mice or AOM/DSS mice in each group. *P<0.05, **P<0.01.
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fig3: AvrA regulates β-catenin activation as assessed by phospho (Ser552) β-catenin in AOM/DSS-induced tumors. (a) β-Catenin localization in control mucosa and colonic tumors. (b) P-β-catenin Ser552 localization in control mucosa and colonic tumors. (c) Quantitation of nuclear P-β-catenin Ser552 in control mucosa and colonic tumors. Data are means±s.d. of n=3 control mice or AOM/DSS tumors in each group. *P<0.05, **P<0.01 (d) Expression levels of p-β-catenin, total β-catenin and Akt and P-Akt as assessed by western blotting in control and AOM/DSS-induced tumors. Shown are control mucosa and tumors representative of three mice in each group. (e) Immunostaining of p-Myc, MMP-7, Cyclin D1 and Bmi1 in control colons and AOM/DSS-induced tumors (left panel). Quantitative imaging of nuclear Bmi1 in control mucosa and mucosa adjacent to tumors (right panel). Data are means±s.d. of n=3 control mice or AOM/DSS mice in each group. *P<0.05, **P<0.01.
Mentions: It is known that β-catenin signaling is activated in colonic tumorigenesis.23 In agreement with previous studies, we observed that nuclear β-catenin was upregulated in AOM/DSS-induced tumors (Figure 3a). Nuclear localization suggested that β-catenin is also activated (Figure 3a).

Bottom Line: In the current study, we colonized mice with Salmonella AvrA-sufficient or AvrA-deficient Salmonella typhimirium strains and induced inflammation-associated colon cancer by azoxymethane/dextran sulfate sodium (AOM/DSS).Tumor incidence in the AvrA+infected group was 100% compared with 51.4% in the AOM/DSS group without bacterial gavage and 56.3% in mice infected with the AvrA- strain.Our observations also raise a note of caution regarding the use of mutant Salmonella organisms as vectors for anti-cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Rush University, Chicago, IL, USA.

ABSTRACT
Salmonella infections can become chronic and increase the risk of cancer. The mechanisms by which specific Salmonella organisms contribute to cancer, however, are still unknown. Live and attenuated Salmonella are used as vectors to target cancer cells, but there have been no systematic studies of the oncogenic potential of chronic Salmonella infections in cancer models. AvrA, a pathogenic product of Salmonella, is inserted into host cells during infection and influences eukaryotic cell pathways. In the current study, we colonized mice with Salmonella AvrA-sufficient or AvrA-deficient Salmonella typhimirium strains and induced inflammation-associated colon cancer by azoxymethane/dextran sulfate sodium (AOM/DSS). We confirmed Salmonella persisted in the colon for up to 45 weeks. Salmonella was identified not only in epithelial cells on the colonic luminal surface and base of the crypts but also in invading tumors. Tumor incidence in the AvrA+infected group was 100% compared with 51.4% in the AOM/DSS group without bacterial gavage and 56.3% in mice infected with the AvrA- strain. Infection with AvrA+ strain also altered tumor distribution from the distal to proximal colon that might reflect changes in the microbiome. AvrA-expressing bacteria also upregulated beta-catenin signaling as assessed by decreased beta-catenin ubiquitination, increased nuclear beta-catenin and increased phosphorylated-beta-catenin (Ser552), a marker of proliferating stem-progenitor cells. Other β-catenin targets increased by AvrA included Bmi1, a cancer stem cell marker, matrix metalloproteinase-7, and cyclin D1. In summary, AvrA-expressing Salmonella infection activates β-catenin signals and enhances colonic tumorigenesis. Our findings provide important new mechanistic insights into how a bacterial protein targets proliferating stem-progenitor cells and contributes to cancer development. Our observations also raise a note of caution regarding the use of mutant Salmonella organisms as vectors for anti-cancer therapy. Finally, these studies could suggest biomarkers (such as AvrA level in gut) to assess cancer risk in susceptible individuals and infection-related dysregulation of β-catenin signaling in cancer.

No MeSH data available.


Related in: MedlinePlus