TY - JOUR
T1 - Association of autophagy status with amount of Fusobacterium nucleatum in colorectal cancer
AU - Haruki, Koichiro
AU - Kosumi, Keisuke
AU - Hamada, Tsuyoshi
AU - Twombly, Tyler S.
AU - Väyrynen, Juha P.
AU - Kim, Sun A.
AU - Masugi, Yohei
AU - Qian, Zhi Rong
AU - Mima, Kosuke
AU - Baba, Yoshifumi
AU - da Silva, Annacarolina
AU - Borowsky, Jennifer
AU - Arima, Kota
AU - Fujiyoshi, Kenji
AU - Lau, Mai Chan
AU - Li, Peilong
AU - Guo, Chunguang
AU - Chen, Yang
AU - Song, Mingyang
AU - Nowak, Jonathan A.
AU - Nishihara, Reiko
AU - Yanaga, Katsuhiko
AU - Zhang, Xuehong
AU - Wu, Kana
AU - Bullman, Susan
AU - Garrett, Wendy S.
AU - Huttenhower, Curtis
AU - Meyerhardt, Jeffrey A.
AU - Giannakis, Marios
AU - Chan, Andrew T.
AU - Fuchs, Charles S.
AU - Ogino, Shuji
N1 - Funding Information:
This work was supported by US National Institutes of Health (NIH) grants (P01 CA87969 to MJ Stampfer; UM1 CA186107 to MJ Stampfer; P01 CA55075 to WC Willett; UM1 CA167552 to WC Willett; U01 CA167552 to WC Willett and LA Mucci; P50 CA127003 to CSF; R01 CA118553 to CSF; R01 CA169141 to CSF; R01 CA137178 to ATC; K24 DK098311 to ATC; R35 CA197735 to SO; R01 CA151993 to SO; K07 CA190673 to RN; and K07 CA188126 to XZ); by Cancer Research UK's Grand Challenge Initiative (C10674/A27140 to WSG, MG, CH, and SO); by Nodal Award (2016-02) from the Dana-Farber Harvard Cancer Center (to SO); by the Stand Up to Cancer Colorectal Cancer Dream Team Translational Research Grant (SU2C-AACR-DT22-17 to CSF. and MG), administered by the American Association for Cancer Research, a scientific partner of SU2C; and by grants from the Project P Fund, The Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance and SU2C. KH was supported by fellowship grants from the Uehara Memorial Foundation and the Mitsukoshi Health and Welfare Foundation. KK was supported by grants from Overseas Research Fellowship (JP2017-0775) from Japan Society for the Promotion of Science and JSPS Fujita Memorial Fund for Medical Research. KA was supported by a grant from Overseas Research Fellowship (JP2018-60083) from Japan Society for the Promotion of Science. JB was supported by a grant from the Australia Awards-Endeavour Scholarships and Fellowships Program. KF was supported by a fellowship grant from the Uehara Memorial Foundation. MG is supported by an ASCO Conquer Cancer Foundation Career Development Award. ATC is a Stuart and Suzanne Steele MGH Research Scholar. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We would like to thank the participants and staff of the Nurses' Health Study and the Health Professionals Follow-up Study for their valuable contributions as well as the following U.S. State cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. The authors assume full responsibility for analyses and interpretation of these data.
Funding Information:
This work was supported by US National Institutes of Health (NIH) grants (P01 CA87969 to MJ Stampfer; UM1 CA186107 to MJ Stampfer; P01 CA55075 to WC Willett; UM1 CA167552 to WC Willett; U01 CA167552 to WC Willett and LA Mucci; P50 CA127003 to CSF; R01 CA118553 to CSF; R01 CA169141 to CSF; R01 CA137178 to ATC; K24 DK098311 to ATC; R35 CA197735 to SO; R01 CA151993 to SO; K07 CA190673 to RN; and K07 CA188126 to XZ); by Cancer Research UK's Grand Challenge Initiative (C10674/A27140 to WSG, MG, CH, and SO); by Nodal Award (2016‐02) from the Dana‐Farber Harvard Cancer Center (to SO); by the Stand Up to Cancer Colorectal Cancer Dream Team Translational Research Grant (SU2C‐AACR‐DT22‐17 to CSF. and MG), administered by the American Association for Cancer Research, a scientific partner of SU2C; and by grants from the Project P Fund, The Friends of the Dana‐Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance and SU2C. KH was supported by fellowship grants from the Uehara Memorial Foundation and the Mitsukoshi Health and Welfare Foundation. KK was supported by grants from Overseas Research Fellowship (JP2017‐0775) from Japan Society for the Promotion of Science and JSPS Fujita Memorial Fund for Medical Research. KA was supported by a grant from Overseas Research Fellowship (JP2018‐60083) from Japan Society for the Promotion of Science. JB was supported by a grant from the Australia Awards‐Endeavour Scholarships and Fellowships Program. KF was supported by a fellowship grant from the Uehara Memorial Foundation. MG is supported by an ASCO Conquer Cancer Foundation Career Development Award. ATC is a Stuart and Suzanne Steele MGH Research Scholar. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - Fusobacterium nucleatum (F. nucleatum), which has been associated with colorectal carcinogenesis, can impair anti-tumour immunity, and actively invade colon epithelial cells. Considering the critical role of autophagy in host defence against microorganisms, we hypothesised that autophagic activity of tumour cells might influence the amount of F. nucleatum in colorectal cancer tissue. Using 724 rectal and colon cancer cases within the Nurses' Health Study and the Health Professionals Follow-up Study, we evaluated autophagic activity of tumour cells by immunohistochemical analyses of BECN1 (beclin 1), MAP1LC3 (LC3), and SQSTM1 (p62) expression. We measured the amount of F. nucleatum DNA in tumour tissue by quantitative polymerase chain reaction (PCR). We conducted multivariable ordinal logistic regression analyses to examine the association of tumour BECN1, MAP1LC3, and SQSTM1 expression with the amount of F. nucleatum, adjusting for potential confounders, including microsatellite instability status; CpG island methylator phenotype; long-interspersed nucleotide element-1 methylation; and KRAS, BRAF, and PIK3CA mutations. Compared with BECN1-low cases, BECN1-intermediate and BECN1-high cases were associated with lower amounts of F. nucleatum with odds ratios (for a unit increase in three ordinal categories of the amount of F. nucleatum) of 0.54 (95% confidence interval, 0.29–0.99) and 0.31 (95% confidence interval, 0.16–0.60), respectively (Ptrend < 0.001 across ordinal BECN1 categories). Tumour MAP1LC3 and SQSTM1 levels were not significantly associated with the amount of F. nucleatum (Ptrend > 0.06). Tumour BECN1, MAP1LC3, and SQSTM1 levels were not significantly associated with patient survival (Ptrend > 0.10). In conclusion, tumour BECN1 expression is inversely associated with the amount of F. nucleatum in colorectal cancer tissue, suggesting a possible role of autophagy in the elimination of invasive microorganisms.
AB - Fusobacterium nucleatum (F. nucleatum), which has been associated with colorectal carcinogenesis, can impair anti-tumour immunity, and actively invade colon epithelial cells. Considering the critical role of autophagy in host defence against microorganisms, we hypothesised that autophagic activity of tumour cells might influence the amount of F. nucleatum in colorectal cancer tissue. Using 724 rectal and colon cancer cases within the Nurses' Health Study and the Health Professionals Follow-up Study, we evaluated autophagic activity of tumour cells by immunohistochemical analyses of BECN1 (beclin 1), MAP1LC3 (LC3), and SQSTM1 (p62) expression. We measured the amount of F. nucleatum DNA in tumour tissue by quantitative polymerase chain reaction (PCR). We conducted multivariable ordinal logistic regression analyses to examine the association of tumour BECN1, MAP1LC3, and SQSTM1 expression with the amount of F. nucleatum, adjusting for potential confounders, including microsatellite instability status; CpG island methylator phenotype; long-interspersed nucleotide element-1 methylation; and KRAS, BRAF, and PIK3CA mutations. Compared with BECN1-low cases, BECN1-intermediate and BECN1-high cases were associated with lower amounts of F. nucleatum with odds ratios (for a unit increase in three ordinal categories of the amount of F. nucleatum) of 0.54 (95% confidence interval, 0.29–0.99) and 0.31 (95% confidence interval, 0.16–0.60), respectively (Ptrend < 0.001 across ordinal BECN1 categories). Tumour MAP1LC3 and SQSTM1 levels were not significantly associated with the amount of F. nucleatum (Ptrend > 0.06). Tumour BECN1, MAP1LC3, and SQSTM1 levels were not significantly associated with patient survival (Ptrend > 0.10). In conclusion, tumour BECN1 expression is inversely associated with the amount of F. nucleatum in colorectal cancer tissue, suggesting a possible role of autophagy in the elimination of invasive microorganisms.
KW - Colorectal neoplasms
KW - Immunology
KW - Microbiology
KW - Microbiome
KW - Molecular pathological epidemiology
KW - Tumour microenvironment
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U2 - 10.1002/path.5381
DO - 10.1002/path.5381
M3 - Article
C2 - 31880318
AN - SCOPUS:85078933979
SN - 0022-3417
VL - 250
SP - 397
EP - 408
JO - Investigative and Cell Pathology
JF - Investigative and Cell Pathology
IS - 4
ER -
