Spatial Expression of IKK-alpha is Associated with a Differential Mutational Landscape and Survival in Primary Colorectal Cancer

Overview

Journal Br J Cancer

Specialty Oncology

Date 2022 Feb 17

PMID 35173303

Authors

Meera Patel

Kathryn A F Pennel

Jean A Quinn

Hannah Hood

David K Chang

Andrew V Biankin

Selma Rebus

Antonia K Roseweir

James H Park

Paul G Horgan

Donald C McMillan

Joanne Edwards

Affiliations

Soon will be listed here.

Abstract

Background: To understand the relationship between key non-canonical NF-κB kinase IKK-alpha(α), tumour mutational profile and survival in primary colorectal cancer.

Methods: Immunohistochemical expression of IKKα was assessed in a cohort of 1030 patients who had undergone surgery for colorectal cancer using immunohistochemistry. Mutational tumour profile was examined using a customised gene panel. Immunofluorescence was used to identify the cellular location of punctate IKKα expression.

Results: Two patterns of IKKα expression were observed; firstly, in the tumour cell cytoplasm and secondly as discrete 'punctate' areas in a juxtanuclear position. Although cytoplasmic expression of IKKα was not associated with survival, high 'punctate' IKKα expression was associated with significantly reduced cancer-specific survival on multivariate analysis. High punctate expression of IKKα was associated with mutations in KRAS and PDGFRA. Dual immunofluorescence suggested punctate IKKα expression was co-located with the Golgi apparatus.

Conclusions: These results suggest the spatial expression of IKKα is a potential biomarker in colorectal cancer. This is associated with a differential mutational profile highlighting possible distinct signalling roles for IKKα in the context of colorectal cancer as well as potential implications for future treatment strategies using IKKα inhibitors.

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References

Patel M, Horgan P, McMillan D, Edwards J . NF-κB pathways in the development and progression of colorectal cancer. Transl Res. 2018; 197:43-56. DOI: 10.1016/j.trsl.2018.02.002. View

Bennett L, Quinn J, McCall P, Mallon E, Horgan P, McMillan D . High IKKα expression is associated with reduced time to recurrence and cancer specific survival in oestrogen receptor (ER)-positive breast cancer. Int J Cancer. 2016; 140(7):1633-1644. DOI: 10.1002/ijc.30578. View

Ammirante M, Luo J, Grivennikov S, Nedospasov S, Karin M . B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature. 2010; 464(7286):302-5. PMC: 2866639. DOI: 10.1038/nature08782. View

Luo J, Tan W, Ricono J, Korchynskyi O, Zhang M, Gonias S . Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin. Nature. 2007; 446(7136):690-4. DOI: 10.1038/nature05656. View

Fernandez-Majada V, Aguilera C, Villanueva A, Vilardell F, Robert-Moreno A, Aytes A . Nuclear IKK activity leads to dysregulated notch-dependent gene expression in colorectal cancer. Proc Natl Acad Sci U S A. 2006; 104(1):276-81. PMC: 1765449. DOI: 10.1073/pnas.0606476104. View

Margalef P, Fernandez-Majada V, Villanueva A, Garcia-Carbonell R, Iglesias M, Lopez L . A truncated form of IKKα is responsible for specific nuclear IKK activity in colorectal cancer. Cell Rep. 2012; 2(4):840-54. DOI: 10.1016/j.celrep.2012.08.028. View

Colomer C, Margalef P, Gonzalez J, Vert A, Bigas A, Espinosa L . IKKα is required in the intestinal epithelial cells for tumour stemness. Br J Cancer. 2018; 118(6):839-846. PMC: 5877427. DOI: 10.1038/bjc.2017.459. View

Anthony N, Baiget J, Berretta G, Boyd M, Breen D, Edwards J . Inhibitory Kappa B Kinase α (IKKα) Inhibitors That Recapitulate Their Selectivity in Cells against Isoform-Related Biomarkers. J Med Chem. 2017; 60(16):7043-7066. PMC: 5578373. DOI: 10.1021/acs.jmedchem.7b00484. View

Kotarski M, Leonard D, Bennett S, BISHOP C, Wahn S, Sedore S . The Drosophila gene asteroid encodes a novel protein and displays dosage-sensitive interactions with Star and Egfr. Genome. 1998; 41(2):295-302. DOI: 10.1139/g98-021. View

10.

Tougeron D, Fauquembergue E, Rouquette A, Le Pessot F, Sesboue R, Laurent M . Tumor-infiltrating lymphocytes in colorectal cancers with microsatellite instability are correlated with the number and spectrum of frameshift mutations. Mod Pathol. 2009; 22(9):1186-95. DOI: 10.1038/modpathol.2009.80. View

11.

Tsukaguchi H, Tokui T, Mackenzie B, Berger U, Chen X, Wang Y . A family of mammalian Na+-dependent L-ascorbic acid transporters. Nature. 1999; 399(6731):70-5. DOI: 10.1038/19986. View

12.

Vreka M, Lilis I, Papageorgopoulou M, Giotopoulou G, Lianou M, Giopanou I . IκB Kinase α Is Required for Development and Progression of -Mutant Lung Adenocarcinoma. Cancer Res. 2018; 78(11):2939-2951. PMC: 6485619. DOI: 10.1158/0008-5472.CAN-17-1944. View

13.

Song N, Zhu F, Wang Z, Willette-Brown J, Xi S, Sun Z . IKKα inactivation promotes Kras-initiated lung adenocarcinoma development through disrupting major redox regulatory pathways. Proc Natl Acad Sci U S A. 2018; 115(4):E812-E821. PMC: 5789942. DOI: 10.1073/pnas.1717520115. View

14.

Eisermann K, Wang D, Jing Y, Pascal L, Wang Z . Androgen receptor gene mutation, rearrangement, polymorphism. Transl Androl Urol. 2014; 2(3):137-147. PMC: 4101814. DOI: 10.3978/j.issn.2223-4683.2013.09.15. View

15.

Guo Z, Yang X, Sun F, Jiang R, Linn D, Chen H . A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res. 2009; 69(6):2305-13. PMC: 2672822. DOI: 10.1158/0008-5472.CAN-08-3795. View

16.

Hu R, Lu C, Mostaghel E, Yegnasubramanian S, Gurel M, Tannahill C . Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer. Cancer Res. 2012; 72(14):3457-62. PMC: 3415705. DOI: 10.1158/0008-5472.CAN-11-3892. View

17.

Song L, Herrell R, Byers S, Shah S, Wilson E, Gelmann E . Beta-catenin binds to the activation function 2 region of the androgen receptor and modulates the effects of the N-terminal domain and TIF2 on ligand-dependent transcription. Mol Cell Biol. 2003; 23(5):1674-87. PMC: 151689. DOI: 10.1128/MCB.23.5.1674-1687.2003. View

18.

Stebbings W, Farthing M, Vinson G, Northover J, Wood R . Androgen receptors in rectal and colonic cancer. Dis Colon Rectum. 1986; 29(2):95-8. DOI: 10.1007/BF02555385. View

19.

Meggouh F, Lointier P, Pezet D, Saez S . Status of sex steroid hormone receptors in large bowel cancer. Cancer. 1991; 67(7):1964-70. DOI: 10.1002/1097-0142(19910401)67:7<1964::aid-cncr2820670724>3.0.co;2-s. View

20.

Castagnetta L, Traina A, Campisi I, Calabro M, Maratta A, Saetta A . Androgen receptor status in nontumoral and malignant human colorectal tissues. Ann N Y Acad Sci. 2002; 963:322-5. DOI: 10.1111/j.1749-6632.2002.tb04124.x. View