Phosphoprotein enriched in diabetes (PED/PEA15) promotes migration in hepatocellular carcinoma and confers resistance to sorafenib

Quintavalle, Cristina; Hindupur, Sravanth K.; Quagliata, Luca; Pallante, Pierlorenzo; Nigro, Cecilia; Condorelli, Gerolama; Andersen, Jesper B.; Tagscherer, Katrin E.; Roth, Wilfried; Béguinot, Francesco; Heim, Markus H.; Ng, Charlotte K.Y.; Piscuoglio, Salvatore; Matter, Matthias S.

doi:10.1038/cddis.2017.512

Cited by 25 publications

(32 citation statements)

References 52 publications

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“…CDDP treatment and PE-15 depletion resulted in significant decreases in the percentage of BrdU-positive cells, and CDDP treatment further reduced the percentage of BrdU-positive SGC7901-PEA low cells, compared with the controls (data not shown and available upon request). Previous studies have revealed that PEA-15 promotes cell proliferation by regulating ERK phosphorylation (9,25). As revealed in Fig.…”

Section: Pea-15 Depletion and Cddp Inhibits Cell Proliferation Bymentioning

confidence: 79%

“…As a multifunctional phosphoprotein, PEA-15 has displayed an important role in several cancer entities (6)(7)(8)(9), but its expression and function have not yet been investigated in gastric cancer. The present study demonstrated that PEA-15 was overexpressed in gastric cancer tissues and cells.…”

Section: Discussionmentioning

confidence: 99%

“…Phosphoprotein enriched in astrocytes 15 (PEA-15), also known as phosphoprotein enriched in diabetes (PED), is ubiquitously expressed in mammals and was originally identified in primary cultured astrocytes (4). PEA-15 was initially found to play a prominent role in controlling cell survival and glucose metabolism (5), and later it was demonstrated to participate in regulating multiple biological behaviors of cells from several types of malignancies including breast and colorectal cancer, and hepatocellular carcinoma (HCC) (6)(7)(8)(9). The well-known mechanism accounting for its function is the regulation of the activation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), which mediate cell proliferation, migration and apoptosis (6,10).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, PEA-15 has recently been demonstrated to contribute to the insensitivity of a panel of chemotherapeutic agents including CDDP in breast cancer (11), resistance to fluorouracil and CDDP in colon cancer (8), and sorafenib resistance in HCC (9). However, it is unclear whether PEA-15 contributes to the mechanisms of CDDP resistance in gastric cancer.…”

Section: Introductionmentioning

confidence: 99%

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PEA‑15 contributes to the clinicopathology and AKT‑regulated cisplatin resistance in gastric cancer

Jiang

Zhang

et al. 2018

Oncol Rep

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Phosphoprotein enriched in astrocytes 15 (PEA-15) plays an important role in controlling biological behaviors of cancer cells. In the present study, we demonstrated that PEA-15 was overexpressed in gastric cancer tissues and associated with tumor staging, differentiation, pathological types and the prognosis of patients. Gastric cancer cells expressed variable levels of PEA-15 and its bi-phosphorylation forms, p-PEA-15 (Ser104) and p-PEA-15 (Ser116). To gain insight into the functional role of PEA-15, we generated cells stably depleted of PEA-15 and resistant to cisplatin (CDDP) from human gastric cancer cells. PEA-15 depletion inhibited cell proliferation by reducing cyclin D1 expression through the extracellular signal-regulated kinase (ERK) pathway, resulting in cell cycle arrest at the G1 phase, and induced apoptosis by activating caspase-8. PEA-15 depletion also enhanced the inhibitory effect of CDDP that caused cell cycle arrest at the S phase and also enhanced the pro-apoptotic activity of CDDP in vitro and in animal models of tumorigenesis and therapeutic effects. PEA-15 and its phosphorylated forms were overexpressed in CDDP-resistant cells, which had higher levels of p-AKT. Specific inhibition of AKT by MK2206 reduced the expression of p-PEA-15 at the Ser116 residue, resulting in sequential downregulation of p-ERK1/2, cyclin D1 and caspase-8 activation. However, depletion of PEA-15 had little effect on AKT expression or phosphorylation, or its downstream factors including p27, glycogen synthase kinase 3β and caspase-9, indicating that the regulatory effects between PEA-15 and AKT were unidirectional. In summary, the results indicated that PEA-15 expression was associated with clinicopathology and prognosis in gastric cancer and was regulated by AKT to participate in CDDP resistance, indicating that it may be a potential target for overcoming CDDP resistance in the treatment of gastric cancer.

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Section: Pea-15 Depletion and Cddp Inhibits Cell Proliferation Bymentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PEA‑15 contributes to the clinicopathology and AKT‑regulated cisplatin resistance in gastric cancer

Jiang

Zhang

et al. 2018

Oncol Rep

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“…Two medications in the first line: Sorafenib, a multikinase inhibitor and Lenvatinib, a multitarget tyrosine kinase VEGFR and FGFR inhibitor, are currently used for the treatment of advanced HCC. [8][9][10] Possible mechanisms inducing resistance to Sorafenib are thought to be autophagy and other pathways 11,12 ; however, precise mechanisms remain elusive. First-line and second-line chemotherapeutic agents, such as Lenvatinib, Pembrolizumab, Ramucirumab, Regorafenib and Cabozantinib, have been approved in an accelerated rate by the FDA in the latest 3 years.…”

Section: Discussionmentioning

confidence: 99%

Hedgehog signalling mediates drug resistance through targeting TAP1 in hepatocellular carcinoma

Zhou

Ding

et al. 2020

J Cellular Molecular Medi

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Multidrug resistance is one of the reasons for low survival of advanced hepatocellular carcinoma (HCC). Our previous studies indicate that the hedgehog signalling is involved in hepatic carcinogenesis, metastasis and chemo-resistance. The present study aims to uncover molecular mechanisms underlying hepatoma chemo-resistance. TAP1 and GLI1/2 gene expression was assessed in both poorly differentiated hepatoma cells and HCC specimens. Potential GLI-binding site in the TAP1 promoter sequence was validated by molecular assays. Approximately 75% HCC specimens exhibited an elevated expression of hedgehog GLI1 transcription factor compared with adjacent liver tissue. Both GLI1/2 and TAP1 protein levels were significantly elevated in poorly differentiated hepatoma cells. Both Huh-7-trans and Huh-7-DN displayed more karyotypic abnormalities and differential gene expression profiles than their native Huh-7 cells. Sensitivity to Sorafenib, doxorubicin and cisplatin was remarkably improved after either GLI1 or TAP1 gene was inhibited by an RNAi approach or by a specific GLI1/2 inhibitor, GANT61. Further experiments confirmed that hedgehog transcription factor GLI1/2 binds to the TAP1 promoter, indicating that TAP1 is one of GLI1/2 target genes. In conclusion, TAP1 is under direct transcriptional control of the hedgehog signalling. Targeting hedgehog signalling confers a novel insight into alleviating drug resistance in the treatment of refractory HCC. K E Y W O R D Schemo-resistance, GANT61, hedgehog signalling, hepatocellular carcinoma, TAP1 | 4299 ZHOU et al.

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Genomic Analysis of Vascular Invasion in HCC Reveals Molecular Drivers and Predictive Biomarkers

Krishnan

Park

et al. 2021

Hepatology

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Background and Aims Vascular invasion (VI) is a critical risk factor for HCC recurrence and poor survival. The molecular drivers of vascular invasion in HCC are open for investigation. Deciphering the molecular landscape of invasive HCC will help identify therapeutic targets and noninvasive biomarkers. Approach and Results To this end, we undertook this study to evaluate the genomic, transcriptomic, and proteomic profile of tumors with VI using the multiplatform cancer genome atlas (The Cancer Genome Atlas; TCGA) data (n = 373). In the TCGA Liver Hepatocellular Carcinoma cohort, macrovascular invasion was present in 5% (n = 17) of tumors and microvascular invasion in 25% (n = 94) of tumors. Functional pathway analysis revealed that the MYC oncogene was a common upstream regulator of the mRNA, miRNA, and proteomic changes in VI. We performed comparative proteomic analyses of invasive human HCC and MYC‐driven murine HCC and identified fibronectin to be a proteomic biomarker of invasive HCC (mouse fibronectin 1 [Fn1], P = 1.7 × 10−11; human FN1, P = 1.5 × 10−4) conserved across the two species. Mechanistically, we show that FN1 promotes the migratory and invasive phenotype of HCC cancer cells. We demonstrate tissue overexpression of fibronectin in human HCC using a large independent cohort of human HCC tissue microarray (n = 153; P < 0.001). Lastly, we showed that plasma fibronectin levels were significantly elevated in patients with HCC (n = 35; mean = 307.7 μg/mL; SEM = 35.9) when compared to cirrhosis (n = 10; mean = 41.8 μg/mL; SEM = 13.3; P < 0.0001). Conclusions Our study evaluates the molecular landscape of tumors with VI, identifying distinct transcriptional, epigenetic, and proteomic changes driven by the MYC oncogene. We show that MYC up‐regulates fibronectin expression, which promotes HCC invasiveness. In addition, we identify fibronectin to be a promising noninvasive proteomic biomarker of VI in HCC.

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Phosphoprotein enriched in diabetes (PED/PEA15) promotes migration in hepatocellular carcinoma and confers resistance to sorafenib

Cited by 25 publications

References 52 publications

PEA‑15 contributes to the clinicopathology and AKT‑regulated cisplatin resistance in gastric cancer

PEA‑15 contributes to the clinicopathology and AKT‑regulated cisplatin resistance in gastric cancer

Hedgehog signalling mediates drug resistance through targeting TAP1 in hepatocellular carcinoma

Genomic Analysis of Vascular Invasion in HCC Reveals Molecular Drivers and Predictive Biomarkers

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