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Is There a Role for Wnt/β‐catenin Modulation in Colorectal Cancer?

By: Melissa E. Fryman, MS
Posted: Wednesday, April 3, 2019

Fusobacterium nucleatum–mediated upregulation of Annexin A1 seems to hasten the progression of colorectal cancer, according to Yiping W. Han, PhD, of the Columbia University College of Dental Medicine, and colleagues. The common oral bacterium F nucleatum preferentially binds cancerous cells with the help of Annexin A1, a newly identified Wnt/ß-catenin modulator. As “inhibition of Annexin A1 suppresses ß-catenin signaling in cancerous cells without affecting the noncancerous cells, [it] may have less adverse ‘off-target’ effects,” wrote the authors. The study findings, which identify therapeutic and diagnostic avenues worthy of exploration, were published in EMBO Reports.

“We propose a two-hit model, where genetic mutations are the first hit. F nucleatum serves as the second hit,” Dr. Han said in a Columbia University press release.

The investigators continued: “In noncancerous cells, there is a low level of Annexin A1 and weak binding of FadA to E-cadherin. In cancerous cells, the Annexin A1 level increases, FadA binding enhances, FadA–E-cadherin–Annexin A1–ß-catenin complex forms, and ß-catenin is activated, resulting in acceleration of cancer progression.”

In this study, cell lines, mouse models, clinical specimens, and RNA-sequencing data were used to test the role of Annexin A1 in colorectal cancer progression. Cancerous (10C, HCT116, and DLD1, SW480, HT29, RKO) and noncancerous (SB) cell lines were used in qualitative polymerase chain reaction, co-immunoprecipitation, flow cytometry, and immunostaining experiments.

Compared with SB cells, F nucleatum was 75% and 150% more efficient at binding and invading 10C cells, and Annexin A1 upregulation in 10C, HCT116, and DLD1 cells was dependent on interaction of FadA adhesin with E-cadherin. Co-immunoprecipitation of DLD1 cell lysates showed FadA, E-cadherin, Annexin A1, and ß-catenin in a physical complex. FadA and Annexin A1 co-localized in cancerous, but not normal, tissues. Xenograft experiments using siRNA against Annexin A1 resulted in significantly smaller tumors compared with controls.

Disclsoure: The study authors’ disclosure information can be found at onlinelibrary.wiley.com.



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