Increased expression of plakophilin 3 is associated with poor prognosis in ovarian cancer

Qian, Hua; Yuan, Donglan; Bao, Jingjing; Liu, Fuxing; Zhang, Wenyan; Yang, Xumei; Han, Gaohua; Huang, Junxing; Sheng, Haihui; Yu, Hong

doi:10.1097/md.0000000000014608

Cited by 10 publications

(9 citation statements)

References 29 publications

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“…In this study, we found that the expression of PKP3 mRNA and protein was upregulated in ovarian cancer and significantly correlated with PFS in patients with ovarian cancer. Qian et al showed that PKP3 was highly expressed in both cytoplasm and nucleus of ovarian cancer, which was consistent with our research, high expression of PKP3 was correlated with advanced FIGO stage, lymph node metastasis, and poor prognosis [ 13 ]. Lim et al .…”

Section: Discussionsupporting

confidence: 91%

“…In terms of potential mechanism, PKP2 could regulate the activity of Wnt/β-catenin in colon cancer-associated fibroblasts [54], and PKP2 promoted the proliferation and migration of lung cancer by activating EGFR signaling pathway [38]. In addition, PKP3 regulated autophagy and invasion of ovarian cancer through MAPK/JNK/ERK1/2/mTOR signaling pathway [13,14]. GO and KEGG enrichment analysis suggested that PKP2/3 and their correlated genes were mainly involved in the formation of plasma membrane, collagen-containing extracellular matrix, cell-cell and anchoring junction.…”

Section: Casesmentioning

confidence: 99%

“…In recent years, many studies have shown that PKP1/2/3 played a well-established role in the occurrence, development, invasion and metastasis of various malignancy, including breast cancer, prostate cancer, gastric cancer [12]. PKP3 could participate in the invasion and metastasis of ovarian cancer [13,14]. However, the expression, prognostic value, biological function and molecular mechanism of PKP1/2/3 in ovarian cancer are not clearly clarified.…”

mentioning

confidence: 99%

“…In this study, on the basis of various bioinformatics databases, we comprehensively and objectively analyzed the relationship between PKP1/2/3 and the occurrence, development, prognostic value and immune infiltration of OC, as well as the related functional regulatory network. As the expression and regulatory mechanism of PKP3 in ovarian cancer has been confirmed by many researchers previously [13,14], the expression and prognosis of PKP2 were further selected for validation with immunohistochemistry, which is helpful to provide a new strategy for early diagnosis and treatment of ovarian cancer.…”

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confidence: 99%

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Identification of PKP 2/3 as potential biomarkers of ovarian cancer based on bioinformatics and experiments

Gao

Guo

et al. 2020

Cancer Cell Int

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Background Plakophilins (PKPs) are widely involved in gene transcription, translation, and signal transduction, playing a crucial role in tumorigenesis and progression. However, the function and potential mechanism of PKP1/2/3 in ovarian cancer (OC) remains unclear. It’s of great value to explore the expression and prognostic values of PKP1/2/3 and their potential mechanisms, immune infiltration in OC. Methods The expression levels, prognostic values and genetic variations of PKP1/2/3 in OC were explored by various bioinformatics tools and databases, and PKP2/3 were selected for further analyzing their regulation network and immune infiltration. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathways (KEGG) enrichment were also conducted. Finally, the expression and prognosis of PKP2 were validated by immunohistochemistry. Results The expression level and prognosis of PKP1 showed little significance in ovarian cancer, and the expression of PKP2/3 mRNA and protein were upregulated in OC, showing significant correlations with poor prognosis of OC. Functional enrichment analysis showed that PKP2/3 and their correlated genes were significantly enriched in adaptive immune response, cytokine receptor activity, organization of cell–cell junction and extracellular matrix; KEGG analysis showed that PKP2/3 and their significantly correlated genes were involved in signaling pathways including cytokine-mediated signaling pathway, receptor signaling pathway and pathways in cancer. Moreover, PKP2/3 were correlated with lymphocytes and immunomodulators. We confirmed that high expression of PKP2 was significantly associated with advanced stage, poor differentiation and poor prognosis of OC patients. Conclusion Members of plakophilins family showed various degrees of abnormal expressions and prognostic values in ovarian cancer. PKP2/3 played crucial roles in tumorigenesis, aggressiveness, malignant biological behavior and immune infiltration of OC, and can be regarded as potential biomarker for early diagnosis and prognosis evaluation in OC.

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Section: Discussionsupporting

confidence: 91%

Section: Casesmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Identification of PKP 2/3 as potential biomarkers of ovarian cancer based on bioinformatics and experiments

Gao

Guo

et al. 2020

Cancer Cell Int

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“…PKP3 is a member of the arm repeat family of catenin proteins and serves as a structural component of desmosomes, mediating cell-cell adhesion and communication [ 21 ]. Recent studies have shown that PKP3 participates in the progression and metastasis of ovarian cancer, prostate cancer and nasopharyngeal carcinoma [ 22 – 24 ], but its molecular mechanism underlying the regulation of antitumor immunity remains unclear. We showed that PKP3 forms protein-RNA complexes with FXR1, which increases the mRNA stability of the deubiquitinase OTUB1.…”

Section: Introductionmentioning

confidence: 99%

N6-methyladenosine-modified circIGF2BP3 inhibits CD8+ T-cell responses to facilitate tumor immune evasion by promoting the deubiquitination of PD-L1 in non-small cell lung cancer

et al. 2021

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Background An in-depth understanding of immune evasion mechanisms in tumors is crucial to overcome resistance and enable innovative advances in immunotherapy. Circular RNAs (circRNAs) have been implicated in cancer progression. However, much remains unknown regarding whether circRNAs impact immune escape in non-small-cell lung carcinoma (NSCLC). Methods We performed bioinformatics analysis to profile and identify the circRNAs mediating immune evasion in NSCLC. A luciferase reporter assay, RNA immunoprecipitation (RIP), RNA pulldown assays and fluorescence in situ hybridization were performed to identify the interactions among circIGF2BP3, miR-328-3p, miR-3173-5p and plakophilin 3 (PKP3). In vitro T cell-mediated killing assays and in vivo syngeneic mouse models were used to investigate the functional roles of circIGF2BP3 and its downstream target PKP3 in antitumor immunity in NSCLC. The molecular mechanism of PKP3-induced PD-L1 upregulation was explored by immunoprecipitation, RIP, and ubiquitination assays. Results We demonstrated that circIGF2BP3 (hsa_circ_0079587) expression was increased in NSCLC and negatively correlated with CD8+ T cell infiltration. Functionally, elevated circIGF2BP3 inactivated cocultured T cells in vitro and compromised antitumor immunity in an immunocompetent mouse model, and this effect was dependent on CD8+ T cells. Mechanistically, METTL3 mediates the N6-methyladenosine (m6A) modification of circIGF2BP3 and promotes its circularization in a manner dependent on the m6A reader protein YTHDC1. circIGF2BP3 competitively upregulates PKP3 expression by sponging miR-328-3p and miR-3173-5p to compromise the cancer immune response. Furthermore, PKP3 engages with the RNA-binding protein FXR1 to stabilize OTUB1 mRNA, and OTUB1 elevates PD-L1 abundance by facilitating its deubiquitination. Tumor PD-L1 deletion completely blocked the impact of the circIGF2BP3/PKP3 axis on the CD8+ T cell response. The inhibition of circIGF2BP3/PKP3 enhanced the treatment efficacy of anti-PD-1 therapy in a Lewis lung carcinoma mouse model. Collectively, the PKP3/PD-L1 signature and the infiltrating CD8+ T cell status stratified NSCLC patients into different risk groups. Conclusion Our results reveal the function of circIGF2BP3 in causing immune escape from CD8+ T cell-mediated killing through a decrease in PD-L1 ubiquitination and subsequent proteasomal degradation by stabilizing OTUB1 mRNA in a PKP3-dependent manner. This work sheds light on a novel mechanism of PD-L1 regulation in NSCLC and provides a rationale to enhance the efficacy of anti-PD-1 treatment in NSCLC.

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Plakophilins and their roles in diseased states

Hofmann

2019

Cell Tissue Res

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Increased expression of plakophilin 3 is associated with poor prognosis in ovarian cancer

Abstract: Supplemental Digital Content is available in the text

Cited by 10 publications

References 29 publications

Identification of PKP 2/3 as potential biomarkers of ovarian cancer based on bioinformatics and experiments

Identification of PKP 2/3 as potential biomarkers of ovarian cancer based on bioinformatics and experiments

N6-methyladenosine-modified circIGF2BP3 inhibits CD8+ T-cell responses to facilitate tumor immune evasion by promoting the deubiquitination of PD-L1 in non-small cell lung cancer

Plakophilins and their roles in diseased states

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