Complement Factor I Promotes Progression of Cutaneous Squamous Cell Carcinoma

Overview

Journal J Invest Dermatol

Publisher Elsevier

Specialty Dermatology

Date 2014 Sep 4

PMID 25184960

Citations 38

Authors

Pilvi Riihila

Liisa Nissinen

Mehdi Farshchian

Atte Kivisaari

Risto Ala-Aho

Markku Kallajoki

Reidar Grenman

Seppo Meri

Sirkku Peltonen

Juha Peltonen

Veli-Matti Kahari

Affiliations

Soon will be listed here.

Abstract

The incidence of cutaneous squamous cell carcinoma (cSCC) is rising worldwide. We have examined the role of complement components in the progression of cSCC. Analysis of cSCC cell lines (n=8) and normal human epidermal keratinocytes (n=11) with whole transcriptome profiling (SOLiD), quantitative real-time reverse transcriptase-PCR, and western blotting revealed marked overexpression of complement factor I (CFI) in cSCC cells. Immunohistochemical analysis for CFI in vivo showed stronger tumor cell-specific labeling intensity in invasive sporadic cSCCs (n=83) and recessive dystrophic epidermolysis bullosa-associated cSCCs (n=7) than in cSCC in situ (n=65), premalignant epidermal lesions (actinic keratoses, n=64), benign epidermal papillomas (seborrheic keratoses, n=39), and normal skin (n=9). The expression of CFI was higher in the aggressive Ha-ras-transformed cell line (RT3) than in less tumorigenic HaCaT cell lines (HaCaT, A5, and II-4). The expression of CFI by cSCC cells was upregulated by IFN-γ and IL-1β. Knockdown of CFI expression inhibited proliferation and migration of cSCC cells and resulted in inhibition of basal extracellular signal-regulated kinase (ERK) 1/2 activation. Knockdown of CFI expression potently inhibited growth of human cSCC xenograft tumors in vivo. These results provide evidence for the role of CFI in the progression of cSCC and identify it as a potential therapeutic target in this nonmelanoma skin cancer.

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References

Rutkowski M, Sughrue M, Kane A, Mills S, Parsa A . Cancer and the complement cascade. Mol Cancer Res. 2010; 8(11):1453-65. DOI: 10.1158/1541-7786.MCR-10-0225. View

Goldberger G, Arnaout M, Aden D, Kay R, Rits M, Colten H . Biosynthesis and postsynthetic processing of human C3b/C4b inactivator (factor I) in three hepatoma cell lines. J Biol Chem. 1984; 259(10):6492-7. View

Julen N, Dauchel H, Lemercier C, Sim R, Fontaine M, Ripoche J . In vitro biosynthesis of complement factor I by human endothelial cells. Eur J Immunol. 1992; 22(1):213-7. DOI: 10.1002/eji.1830220131. View

Tufaro A, Chuang J, Prasad N, Chuang A, Chuang T, Fischer A . Molecular markers in cutaneous squamous cell carcinoma. Int J Surg Oncol. 2012; 2011:231475. PMC: 3265276. DOI: 10.1155/2011/231475. View

Riihila P, Nissinen L, Ala-Aho R, Kallajoki M, Grenman R, Meri S . Complement factor H: a biomarker for progression of cutaneous squamous cell carcinoma. J Invest Dermatol. 2013; 134(2):498-506. DOI: 10.1038/jid.2013.346. View

Okroj M, Hsu Y, Ajona D, Pio R, Blom A . Non-small cell lung cancer cells produce a functional set of complement factor I and its soluble cofactors. Mol Immunol. 2007; 45(1):169-79. DOI: 10.1016/j.molimm.2007.04.025. View

Boukamp P, Petrussevska R, Breitkreutz D, Hornung J, Markham A, Fusenig N . Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J Cell Biol. 1988; 106(3):761-71. PMC: 2115116. DOI: 10.1083/jcb.106.3.761. View

Schulze M, Pruchno C, Burns M, Baker P, Johnson R, Couser W . Glomerular C3c localization indicates ongoing immune deposit formation and complement activation in experimental glomerulonephritis. Am J Pathol. 1993; 142(1):179-87. PMC: 1886837. View

Mueller M, Peter W, Mappes M, Huelsen A, STEINBAUER H, Boukamp P . Tumor progression of skin carcinoma cells in vivo promoted by clonal selection, mutagenesis, and autocrine growth regulation by granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. Am J Pathol. 2001; 159(4):1567-79. PMC: 1850484. DOI: 10.1016/S0002-9440(10)62541-2. View

10.

Vetvicka V, Reed W, HOOVER M, Ross G . Complement factors H and I synthesized by B cell lines function to generate a growth factor activity from C3. J Immunol. 1993; 150(9):4052-60. View

11.

Timar K, Dallos A, Kiss M, Husz S, Bos J, Asghar S . Expression of terminal complement components by human keratinocytes. Mol Immunol. 2007; 44(10):2578-86. DOI: 10.1016/j.molimm.2006.12.014. View

12.

Zipfel P, Skerka C . Complement regulators and inhibitory proteins. Nat Rev Immunol. 2009; 9(10):729-40. DOI: 10.1038/nri2620. View

13.

Reca R, Cramer D, Yan J, Laughlin M, Janowska-Wieczorek A, Ratajczak J . A novel role of complement in mobilization: immunodeficient mice are poor granulocyte-colony stimulating factor mobilizers because they lack complement-activating immunoglobulins. Stem Cells. 2007; 25(12):3093-100. DOI: 10.1634/stemcells.2007-0525. View

14.

Nilsson S, Sim R, Lea S, Fremeaux-Bacchi V, Blom A . Complement factor I in health and disease. Mol Immunol. 2011; 48(14):1611-20. DOI: 10.1016/j.molimm.2011.04.004. View

15.

Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S . Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med. 1998; 4(7):844-7. DOI: 10.1038/nm0798-844. View

16.

Nagasawa S, Stroud R . Mechanism of action of the C3b inactivator: requirement for a high molecular weight cofactor (C3b-C4bINA cofactor) and production of a new C3b derivative (C3b'). Immunochemistry. 1977; 14(11-12):749-56. DOI: 10.1016/0019-2791(77)90345-7. View

17.

Timar K, Junnikkala S, Dallos A, Jarva H, Bhuiyan Z, Meri S . Human keratinocytes produce the complement inhibitor factor I: Synthesis is regulated by interferon-gamma. Mol Immunol. 2007; 44(11):2943-9. DOI: 10.1016/j.molimm.2007.01.007. View

18.

Dovezenski N, Billetta R, Gigli I . Expression and localization of proteins of the complement system in human skin. J Clin Invest. 1992; 90(5):2000-12. PMC: 443264. DOI: 10.1172/JCI116080. View

19.

Rutkowski M, Sughrue M, Kane A, Ahn B, Fang S, Parsa A . The complement cascade as a mediator of tissue growth and regeneration. Inflamm Res. 2010; 59(11):897-905. PMC: 2945462. DOI: 10.1007/s00011-010-0220-6. View

20.

Vyse T, Morley B, BARTOK I, Theodoridis E, Davies K, Webster A . The molecular basis of hereditary complement factor I deficiency. J Clin Invest. 1996; 97(4):925-33. PMC: 507137. DOI: 10.1172/JCI118515. View