Comprehensive Analysis Identifies PKP3 Overexpression in Pancreatic Cancer Related to Unfavorable Prognosis

Overview

Journal Biomedicines

Specialty Biomedical Engineering

Date 2023 Sep 28

PMID 37760912

Authors

Yan Du

Shuang Hou

Zhou Chen

Wancheng Li

Xin Li

Wence Zhou

Affiliations

Soon will be listed here.

Abstract

Plakophilin 3 (PKP3) affects cell signal transduction and cell adhesion and performs a crucial function in tumorigenesis. The current investigation evaluated the predictive significance and underlying processes of PKP3 within pancreatic cancer (PC) tissues. The assessment of differences in PKP3 expression was conducted through an analysis of RNA-seq data acquired from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Additionally, clinical samples were collected to validate the findings. The predictive significance of PKP3 was investigated by analyzing survival data derived from TCGA and clinical specimens. PKP3's biological function was assessed via phenotypic experiments after the suppression of PKP3 expression within PC cells. Functional enrichment analysis, encompassing KEGG, GO, and GSEA, was employed to assess the underlying mechanism of PKP3. Immune infiltration analysis was conducted in the present investigation to determine the association between PKP3 and tumor-infiltrating immune cells (TICs). In PC tissues, PKP3 expression was abnormally upregulated and correlated with a negative prognosis in individuals with PC. PKP3 can promote the progression, migration, and invasive capacity of PC cells and is relevant to the regulation of the PI3K-Akt and MAPK signaling pathways. Immune infiltration analysis demonstrated that PKP3 impeded CD8+ T-cell infiltration and immune cytokine expression within the tumor microenvironment. The PKP3 protein was identified as a prospective independent predictive indicator and represents a viable approach for immunotherapy in the context of PC. PKP3 may impact prognosis by broadly inhibiting immune cell infiltration and promoting the activation of tumor-associated signaling pathways.

Citing Articles

A Comparison of Tools That Identify Tumor Cells by Inferring Copy Number Variations from Single-Cell Experiments in Pancreatic Ductal Adenocarcinoma.

Oketch D, Giulietti M, Piva F Biomedicines. 2024; 12(8).

PMID: 39200223 PMC: 11351975. DOI: 10.3390/biomedicines12081759.

References

Kumar S, Singh S, Srivastava P, Suresh S, Rana B, Rana A . Interplay between MAP kinases and tumor microenvironment: Opportunity for immunotherapy in pancreatic cancer. Adv Cancer Res. 2023; 159:113-143. DOI: 10.1016/bs.acr.2023.02.003. View

Grossberg A, Chu L, Deig C, Fishman E, Hwang W, Maitra A . Multidisciplinary standards of care and recent progress in pancreatic ductal adenocarcinoma. CA Cancer J Clin. 2020; 70(5):375-403. PMC: 7722002. DOI: 10.3322/caac.21626. View

Gosavi P, Kundu S, Khapare N, Sehgal L, Karkhanis M, Dalal S . E-cadherin and plakoglobin recruit plakophilin3 to the cell border to initiate desmosome assembly. Cell Mol Life Sci. 2010; 68(8):1439-54. PMC: 11114901. DOI: 10.1007/s00018-010-0531-3. View

Goldman M, Craft B, Hastie M, Repecka K, McDade F, Kamath A . Visualizing and interpreting cancer genomics data via the Xena platform. Nat Biotechnol. 2020; 38(6):675-678. PMC: 7386072. DOI: 10.1038/s41587-020-0546-8. View

Bass-Zubek A, Godsel L, Delmar M, Green K . Plakophilins: multifunctional scaffolds for adhesion and signaling. Curr Opin Cell Biol. 2009; 21(5):708-16. PMC: 3091506. DOI: 10.1016/j.ceb.2009.07.002. View

Brooke M, Nitoiu D, Kelsell D . Cell-cell connectivity: desmosomes and disease. J Pathol. 2011; 226(2):158-71. DOI: 10.1002/path.3027. View

Yin L, Lu Y, Cao C, Lu Z, Wei J, Zhu X . CA9-Related Acidic Microenvironment Mediates CD8+ T Cell Related Immunosuppression in Pancreatic Cancer. Front Oncol. 2022; 11:832315. PMC: 8828571. DOI: 10.3389/fonc.2021.832315. View

Braicu C, Buse M, Busuioc C, Drula R, Gulei D, Raduly L . A Comprehensive Review on MAPK: A Promising Therapeutic Target in Cancer. Cancers (Basel). 2019; 11(10). PMC: 6827047. DOI: 10.3390/cancers11101618. View

Rietscher K, Keil R, Jordan A, Hatzfeld M . 14-3-3 proteins regulate desmosomal adhesion via plakophilins. J Cell Sci. 2018; 131(10). DOI: 10.1242/jcs.212191. View

10.

Vasaikar S, Straub P, Wang J, Zhang B . LinkedOmics: analyzing multi-omics data within and across 32 cancer types. Nucleic Acids Res. 2017; 46(D1):D956-D963. PMC: 5753188. DOI: 10.1093/nar/gkx1090. View

11.

Basu S, Thorat R, Dalal S . MMP7 is required to mediate cell invasion and tumor formation upon Plakophilin3 loss. PLoS One. 2015; 10(4):e0123979. PMC: 4395386. DOI: 10.1371/journal.pone.0123979. View

12.

Edgar R, Domrachev M, Lash A . Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2001; 30(1):207-10. PMC: 99122. DOI: 10.1093/nar/30.1.207. View

13.

Werner J, Combs S, Springfeld C, Hartwig W, Hackert T, Buchler M . Advanced-stage pancreatic cancer: therapy options. Nat Rev Clin Oncol. 2013; 10(6):323-33. DOI: 10.1038/nrclinonc.2013.66. View

14.

Breuninger S, Reidenbach S, Sauer C, Strobel P, Pfitzenmaier J, Trojan L . Desmosomal plakophilins in the prostate and prostatic adenocarcinomas: implications for diagnosis and tumor progression. Am J Pathol. 2010; 176(5):2509-19. PMC: 2861115. DOI: 10.2353/ajpath.2010.090737. View

15.

Looi C, Chung F, Leong C, Wong S, Rosli R, Mai C . Therapeutic challenges and current immunomodulatory strategies in targeting the immunosuppressive pancreatic tumor microenvironment. J Exp Clin Cancer Res. 2019; 38(1):162. PMC: 6463646. DOI: 10.1186/s13046-019-1153-8. View

16.

Gbolahan O, Tong Y, Sehdev A, ONeil B, Shahda S . Overall survival of patients with recurrent pancreatic cancer treated with systemic therapy: a retrospective study. BMC Cancer. 2019; 19(1):468. PMC: 6525379. DOI: 10.1186/s12885-019-5630-4. View

17.

Lutz V, Hellmund V, Picard F, Raifer H, Ruckenbrod T, Klein M . IL18 Receptor Signaling Regulates Tumor-Reactive CD8+ T-cell Exhaustion via Activation of the IL2/STAT5/mTOR Pathway in a Pancreatic Cancer Model. Cancer Immunol Res. 2023; 11(4):421-434. DOI: 10.1158/2326-6066.CIR-22-0398. View

18.

Siegel R, Miller K, Fuchs H, Jemal A . Cancer statistics, 2022. CA Cancer J Clin. 2022; 72(1):7-33. DOI: 10.3322/caac.21708. View

19.

Muller L, Keil R, Hatzfeld M . Plakophilin 3 facilitates G1/S phase transition and enhances proliferation by capturing RB protein in the cytoplasm and promoting EGFR signaling. Cell Rep. 2023; 42(1):112031. DOI: 10.1016/j.celrep.2023.112031. View

20.

Hobbs R, Green K . Desmoplakin regulates desmosome hyperadhesion. J Invest Dermatol. 2011; 132(2):482-5. PMC: 3461275. DOI: 10.1038/jid.2011.318. View