Apigenin Targets MicroRNA-155, Enhances SHIP-1 Expression, and Augments Anti-Tumor Responses in Pancreatic Cancer

Kazim Husain; Krystal Villalobos-Ayala; Valentina Laverde; Oscar A. Vazquez; Bradley Miller; Samra Kazim; George Blanck; Margaret L. Hibbs; Gerald Krystal; Isra Elhussin; Joakin Mori; Clayton Yates; Tomar Ghansah

doi:10.3390/cancers14153613

Cancers (Jul 2022)

Apigenin Targets MicroRNA-155, Enhances SHIP-1 Expression, and Augments Anti-Tumor Responses in Pancreatic Cancer

Kazim Husain,
Krystal Villalobos-Ayala,
Valentina Laverde,
Oscar A. Vazquez,
Bradley Miller,
Samra Kazim,
George Blanck,
Margaret L. Hibbs,
Gerald Krystal,
Isra Elhussin,
Joakin Mori,
Clayton Yates,
Tomar Ghansah

Affiliations

Kazim Husain: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
Krystal Villalobos-Ayala: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
Valentina Laverde: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
Oscar A. Vazquez: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
Bradley Miller: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
Samra Kazim: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
George Blanck: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
Margaret L. Hibbs: Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne 3004, Australia
Gerald Krystal: The Terry Fox Laboratory, BC Cancer, Vancouver, BC V5Z 1L3, Canada
Isra Elhussin: Department of Biology and Center for Cancer Research, Tuskegee University, Tuskegee, AL 36088, USA
Joakin Mori: Department of Biology and Center for Cancer Research, Tuskegee University, Tuskegee, AL 36088, USA
Clayton Yates: Department of Biology and Center for Cancer Research, Tuskegee University, Tuskegee, AL 36088, USA
Tomar Ghansah: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA

DOI: https://doi.org/10.3390/cancers14153613
Journal volume & issue: Vol. 14, no. 15
p. 3613

Abstract

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Pancreatic cancer (PC) is a deadly disease with a grim prognosis. Pancreatic tumor derived factors (TDF) contribute to the induction of an immunosuppressive tumor microenvironment (TME) that impedes the effectiveness of immunotherapy. PC-induced microRNA-155 (miRNA-155) represses expression of Src homology 2 (SH2) domain-containing Inositol 5′-phosphatase-1 (SHIP-1), a regulator of myeloid cell development and function, thus impacting anti-tumor immunity. We recently reported that the bioflavonoid apigenin (API) increased SHIP-1 expression which correlated with the expansion of tumoricidal macrophages (TAM) and improved anti-tumor immune responses in the TME of mice with PC. We now show that API transcriptionally regulates SHIP-1 expression via the suppression of miRNA-155, impacting anti-tumor immune responses in the bone marrow (BM) and TME of mice with PC. We discovered that API reduced miRNA-155 in the PC milieu, which induced SHIP-1 expression. This promoted the restoration of myelopoiesis and increased anti-tumor immune responses in the TME of heterotopic, orthotopic and transgenic SHIP-1 knockout preclinical mouse models of PC. Our results suggest that manipulating SHIP-1 through miR-155 may assist in augmenting anti-tumor immune responses and aid in the therapeutic intervention of PC.

Published in Cancers

ISSN: 2072-6694 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.mdpi.com/journal/cancers/

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