Plakophilin 1 enhances MYC translation, promoting squamous cell lung cancer

Martín-Padrón, Joel; Boyero, Laura; Rodríguez, María I.; Andrades, Álvaro; Díaz-Cano, Inés; Peinado, Paola; Baliñas-Gavira, Carlos; Álvarez-Pérez, Juan Carlos; Coira, Isabel F.; Fárez-Vidal, María Esther; Medina, Pedro

doi:10.1038/s41388-019-1129-3

Cited by 20 publications

(18 citation statements)

References 29 publications

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“…DSC2 and PKP1 have been reported to be both oncogenes and tumor suppressors in previous studies ( 23 , 52 – 56 ). In this study, we found that high levels of DSC2 and PKP1 were also important for maintaining the high expression of VIM, which subsequently stimulated FN1/ITGB1/FAK/Src/MEK/ERK/ZEB1-mediated metastasis.…”

Section: Discussionmentioning

confidence: 82%

Desmosomal proteins of DSC2 and PKP1 promote cancer cells survival and metastasis by increasing cluster formation in circulatory system

Zhou

et al. 2021

Sci. Adv.

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To study how cancer cells can withstand fluid shear stress (SS), we isolated SS-resistant breast and lung cancer cells using a microfluidic circulatory system. These SS-resistant cells showed higher abilities to form clusters, survive in circulation, and metastasize in mice. These SS-resistant cells expressed 4.2-to 5.3-fold more desmocollin-2 (DSC2) and plakophilin-1 (PKP1) proteins. The high expression of DSC2 and PKP1 facilitated cancer cells to form clusters in circulation, and also activated PI3K/AKT/Bcl-2-mediated pathway to increase cell survival. The high levels of DSC2 and PKP1 are also important for maintaining high expression of vimentin, which stimulates fibronectin/ integrin  1 /FAK/Src/MEK/ERK/ZEB1-mediated metastasis. Moreover, higher levels of DSC2 and PKP1 were detected in tumor samples from patients with breast and lung cancer, and their high expression was correlated with lower overall survival and worse disease progression. DSC2 and PKP1 may serve as new biomarkers for detecting and targeting metastatic circulating tumor cells.

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Section: Discussionmentioning

confidence: 82%

Desmosomal proteins of DSC2 and PKP1 promote cancer cells survival and metastasis by increasing cluster formation in circulatory system

Zhou

et al. 2021

Sci. Adv.

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“…The protein networks of the WM26 module demonstrated the involvement of upregulated desmosomal proteins including DSP, DSC2 (desmocollin 2), DSC3 (desmocollin 3), JUP (junction plakoglobin), PKP1 (plakophilin 1), and PKP3 (plakophilin 3). Martin-Padron et al reported that PKP1 was overexpressed and increased cell proliferation and cell survival in lung SqCC, and found that PKP1 enhances MYC translation together with the translation initiation complex by binding to the MYC mRNA 44 . Kudo et al demonstrated via immunohistochemical staining that the expression of DSC3 , SFN , DSP , and JUP among cell adhesion and growth inhibitor genes was highly increased in TP53 -mutated tumors and that TP53 -mutated tumors exhibited high nuclear staining of the TP53 protein only in tumor cells at the tumor margins adjacent to the stroma but not in the tumor interior; thus, exhibiting tumor cell heterogeneity in the expression of mutated TP53 protein between the tumor interior and margins 45 .…”

Section: Resultsmentioning

confidence: 99%

Protein co-expression network-based profiles revealed from laser-microdissected cancerous cells of lung squamous-cell carcinomas

Nishimura

Fujii

Nakamura

et al. 2021

Sci Rep

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No therapeutic targets have been identified for lung squamous cell cancer (SqCC) which is the second most prevalent lung cancer because its molecular profiles remain unclear. This study aimed to unveil disease-related protein networks by proteomic and bioinformatic assessment of laser-microdissected cancerous cells from seven SqCCs compared with eight representative lung adenocarcinomas. We identified three network modules significant to lung SqCC using weighted gene co-expression network analysis. One module was intrinsically annotated to keratinization and cell proliferation of SqCC, accompanied by hypoxia-induced aerobic glycolysis, in which key regulators were activated (HIF1A, ROCK2, EFNA1-5) and highly suppressed (KMT2D). The other two modules were significant for translational initiation, nonsense-mediated mRNA decay, inhibited cell death, and interestingly, eIF2 signaling, in which key regulators, MYC and MLXIPL, were highly activated. Another key regulator LARP1, the master regulator in cap-dependent translation, was highly suppressed although upregulations were observed for hub proteins including EIF3F and LARP1 targeted ribosomal proteins, among which PS25 is the key ribosomal protein in IRES-dependent translation. Our results suggest an underlying progression mechanism largely caused by switching to the cap-independent, IRES-dependent translation of mRNA subsets encoding oncogenic proteins. Our findings may help to develop therapeutic strategies to improve patient outcomes.

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“…Many studies have suggested that the expression of PKP1 was significantly decreased or deleted in malignant tumors, including oral/pharyngeal squamous cell carcinoma, esophageal squamous cell carcinoma, prostate cancer [ 30 – 32 ], and high expression of PKP1 inhibited proliferation, migration and invasion of these tumors, suggesting that PKP1 may be served as a tumor suppressor gene. Recent studies have shown that knockout of PKP1 by CRISPR-Cas9 technique significantly inhibited tumor proliferation and promoted metastasis and dissemination of lung cancer, and PKP1 promoted MYC translation by binding 5′-UTR of MYC mRNA, suggesting that PKP1 was also recognized as an oncogene in lung cancer [ 33 ]. In this study, we found that the levels of PKP1 mRNA and protein were not significantly upregulated in ovarian cancer, indicating that PKP1 may not exert valuable function in occurrence and development of ovarian cancer, but the research need to be further verified by larger clinical samples and experimental evidence.…”

Section: Discussionmentioning

confidence: 99%

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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Plakophilin 1 enhances MYC translation, promoting squamous cell lung cancer

Cited by 20 publications

References 29 publications

Desmosomal proteins of DSC2 and PKP1 promote cancer cells survival and metastasis by increasing cluster formation in circulatory system

Desmosomal proteins of DSC2 and PKP1 promote cancer cells survival and metastasis by increasing cluster formation in circulatory system

Protein co-expression network-based profiles revealed from laser-microdissected cancerous cells of lung squamous-cell carcinomas

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

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