PRKCI Promotes Immune Suppression in Ovarian Cancer

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2017 Jul 13

PMID 28698296

Citations 48

Authors

Sharmistha Sarkar

Christopher A Bristow

Prasenjit Dey

Kunal Rai

Ruth Perets

Alejandra Ramirez-Cardenas

Shruti Malasi

Emmet Huang-Hobbs

Monika Haemmerle

Sherry Y Wu

Michael McGuire

Alexei Protopopov

Shan Jiang

Joyce F Liu

Michelle S Hirsch

Qing Chang

Alexander J Lazar

Anil K Sood

Ronny Drapkin

Ronald DePinho

Giulio Draetta

Lynda Chin

Affiliations

Soon will be listed here.

Abstract

A key feature of high-grade serous ovarian carcinoma (HGSOC) is frequent amplification of the 3q26 locus harboring (). Here, we show that PRKCI is also expressed in early fallopian tube lesions, called serous tubal intraepithelial carcinoma. Transgenic mouse studies establish as an ovarian cancer-specific oncogene. Mechanistically, we show that the oncogenic activity of PRKCI relates in part to the up-regulation of TNFα to promote an immune-suppressive tumor microenvironment characterized by an abundance of myeloid-derived suppressor cells and inhibition of cytotoxic T-cell infiltration. Furthermore, system-level and functional analyses identify YAP1 as a downstream effector in tumor progression. In human ovarian cancers, high PRKCI expression also correlates with high expression of TNFα and YAP1 and low infiltration of cytotoxic T cells. The PRKCI-YAP1 regulation of the tumor immunity provides a therapeutic strategy for highly lethal ovarian cancer.

Citing Articles

Cellular polarity pilots breast cancer progression and immunosuppression.

Huang J, Luo S, Shen J, Lee M, Chen R, Ma S Oncogene. 2025; .

PMID: 40057606 DOI: 10.1038/s41388-025-03324-0.

miR-630 as a therapeutic target in pancreatic cancer stem cells: modulation of the PRKCI-Hedgehog signaling axis.

Zou J, Yang S, He C, Deng L, Xu B, Chen S Biol Direct. 2024; 19(1):109.

PMID: 39529141 PMC: 11555831. DOI: 10.1186/s13062-024-00539-1.

PKC inhibitors promote breast cancer immune evasion by maintaining PD-L1 stability.

Yu J, Xiang Y, Gao Y, Chang S, Kong R, Lv X Acta Pharm Sin B. 2024; 14(10):4378-4395.

PMID: 39525583 PMC: 11544271. DOI: 10.1016/j.apsb.2024.08.003.

Epigenome-Wide DNA Methylation in Unipolar Depression: Predictive Biomarker of Antidepressant Treatment Response?.

Schiele M, Crespo Salvador O, Lipovsek J, Schwarte K, Schlosser P, Zwanzger P Int J Neuropsychopharmacol. 2024; 27(11).

PMID: 39367879 PMC: 11558245. DOI: 10.1093/ijnp/pyae045.

Multidimensional analysis of tumor stem cells: from biological properties, metabolic adaptations to immune escape mechanisms.

Han H, He T, Wu Y, He T, Zhou W Front Cell Dev Biol. 2024; 12:1441081.

PMID: 39184916 PMC: 11341543. DOI: 10.3389/fcell.2024.1441081.

References

Zhang L, Conejo-Garcia J, Katsaros D, Gimotty P, Massobrio M, Regnani G . Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003; 348(3):203-13. DOI: 10.1056/NEJMoa020177. View

Murray N, Jamieson L, Yu W, Zhang J, Gokmen-Polar Y, Sier D . Protein kinase Ciota is required for Ras transformation and colon carcinogenesis in vivo. J Cell Biol. 2004; 164(6):797-802. PMC: 2172278. DOI: 10.1083/jcb.200311011. View

Regala R, Weems C, Jamieson L, Copland J, Thompson E, Fields A . Atypical protein kinase Ciota plays a critical role in human lung cancer cell growth and tumorigenicity. J Biol Chem. 2005; 280(35):31109-15. DOI: 10.1074/jbc.M505402200. View

Takagawa R, Akimoto K, Ichikawa Y, Akiyama H, Kojima Y, Ishiguro H . High expression of atypical protein kinase C lambda/iota in gastric cancer as a prognostic factor for recurrence. Ann Surg Oncol. 2009; 17(1):81-8. DOI: 10.1245/s10434-009-0708-x. View

Li H, Han Y, Guo Q, Zhang M, Cao X . Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1. J Immunol. 2008; 182(1):240-9. DOI: 10.4049/jimmunol.182.1.240. View

Tong G, Chiriboga L, Hamele-Bena D, Borczuk A . Expression of PAX2 in papillary serous carcinoma of the ovary: immunohistochemical evidence of fallopian tube or secondary Müllerian system origin?. Mod Pathol. 2007; 20(8):856-63. DOI: 10.1038/modpathol.3800827. View

Szlosarek P, Grimshaw M, Kulbe H, Wilson J, Wilbanks G, Burke F . Expression and regulation of tumor necrosis factor alpha in normal and malignant ovarian epithelium. Mol Cancer Ther. 2006; 5(2):382-90. DOI: 10.1158/1535-7163.MCT-05-0303. View

Obermajer N, Muthuswamy R, Odunsi K, Edwards R, Kalinski P . PGE(2)-induced CXCL12 production and CXCR4 expression controls the accumulation of human MDSCs in ovarian cancer environment. Cancer Res. 2011; 71(24):7463-70. PMC: 4993027. DOI: 10.1158/0008-5472.CAN-11-2449. View

Ginos M, Page G, Michalowicz B, Patel K, Volker S, Pambuccian S . Identification of a gene expression signature associated with recurrent disease in squamous cell carcinoma of the head and neck. Cancer Res. 2004; 64(1):55-63. DOI: 10.1158/0008-5472.can-03-2144. View

10.

Kojima Y, Akimoto K, Nagashima Y, Ishiguro H, Shirai S, Chishima T . The overexpression and altered localization of the atypical protein kinase C lambda/iota in breast cancer correlates with the pathologic type of these tumors. Hum Pathol. 2008; 39(6):824-31. DOI: 10.1016/j.humpath.2007.11.001. View

11.

Zhao X, Rong L, Zhao X, Li X, Liu X, Deng J . TNF signaling drives myeloid-derived suppressor cell accumulation. J Clin Invest. 2012; 122(11):4094-104. PMC: 3484453. DOI: 10.1172/JCI64115. View

12.

Eder A, Sui X, Rosen D, Nolden L, Cheng K, Lahad J . Atypical PKCiota contributes to poor prognosis through loss of apical-basal polarity and cyclin E overexpression in ovarian cancer. Proc Natl Acad Sci U S A. 2005; 102(35):12519-24. PMC: 1188258. DOI: 10.1073/pnas.0505641102. View

13.

Grivennikov S, Greten F, Karin M . Immunity, inflammation, and cancer. Cell. 2010; 140(6):883-99. PMC: 2866629. DOI: 10.1016/j.cell.2010.01.025. View

14.

Mahmoud S, Paish E, Powe D, Macmillan R, Grainge M, Lee A . Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011; 29(15):1949-55. DOI: 10.1200/JCO.2010.30.5037. View

15.

Curiel T, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P . Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004; 10(9):942-9. DOI: 10.1038/nm1093. View

16.

Pinciroli P, Alberti C, Sensi M, Canevari S, Tomassetti A . An IL6-correlated signature in serous epithelial ovarian cancer associates with growth factor response. BMC Genomics. 2013; 14:508. PMC: 3728068. DOI: 10.1186/1471-2164-14-508. View

17.

Wang G, Lu X, Dey P, Deng P, Wu C, Jiang S . Targeting YAP-Dependent MDSC Infiltration Impairs Tumor Progression. Cancer Discov. 2015; 6(1):80-95. PMC: 4707102. DOI: 10.1158/2159-8290.CD-15-0224. View

18.

Ness R, Cottreau C . Possible role of ovarian epithelial inflammation in ovarian cancer. J Natl Cancer Inst. 1999; 91(17):1459-67. DOI: 10.1093/jnci/91.17.1459. View

19.

Charles K, Kulbe H, Soper R, Escorcio-Correia M, Lawrence T, Schultheis A . The tumor-promoting actions of TNF-alpha involve TNFR1 and IL-17 in ovarian cancer in mice and humans. J Clin Invest. 2009; 119(10):3011-23. PMC: 2752076. DOI: 10.1172/JCI39065. View

20.

Menendez J, Perez-Garijo A, Calleja M, Morata G . A tumor-suppressing mechanism in Drosophila involving cell competition and the Hippo pathway. Proc Natl Acad Sci U S A. 2010; 107(33):14651-6. PMC: 2930466. DOI: 10.1073/pnas.1009376107. View