Expression of the PTEN/FOXO3a/PLZF signalling pathway in pancreatic cancer and its significance in tumourigenesis and progression

Zhang, Qiubo; Li, Xuanna; Li, Yaqing; Chen, Shaojie; Shen, Xiaoling; Dong, Xianwen; Song, Yufei; Huang, Kaihong

doi:10.1007/s10637-019-00791-7

Cited by 19 publications

(17 citation statements)

References 36 publications

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“…Moreover, miR‐23a‐3p has been reported to function as an oncogenic regulator of pancreatic cancer 12 . Existing literature has reported that FOXO3 is poorly expressed in pancreatic cancer, thus signifying its vital significance in tumorigenesis and cancer development, 36 which was consistent with our finding. Essentially, miR‐23a‐3p could evidently target the downstream target gene so as to regulate cancer progression 37 .…”

Section: Discussionsupporting

confidence: 91%

LINC00472 suppressed by ZEB1 regulates the miR‐23a‐3p/FOXO3/BID axis to inhibit the progression of pancreatic cancer

Wang

2021

J Cellular Molecular Medi

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The tumour‐suppressive role of LINC00472 has been extensively reported in various human cancers such as lung, colon and ovarian cancers, yet its function in pancreatic cancer remains unidentified. Here, the current research aimed to explore the role and regulatory axis mediated by LINC00472 in the progression of pancreatic cancer. RT‐qPCR was adopted to determine LINC00472 expression in the harvested pancreatic cancer tissues and adjacent normal tissues. Loss‐of‐function and gain‐of‐function experiments were performed to examine the effects of LINC00472 on proliferation and apoptosis in vitro and tumorigenesis in vivo. Immunoblotting was performed to detect the expression of several proliferation and apoptosis‐related proteins. Bioinformatic analysis, dual‐luciferase reporter assay and RNA pull‐down were conducted to profile the relationships between LINC00472 and miR‐23a‐3p, between miR‐23a‐3p and FOXO3 and between FOXO3 and BID. The LINC00472 expression was down‐regulated by ZEB1 in the pancreatic cancer cells and tissues. LINC00472 could competitively bind to miR‐23a‐3p to enhance the expression of FOXO3, which consequently could promote the BID expression, thereby suppressing proliferation and promoting the apoptosis of pancreatic cancer cells. Meanwhile, the inhibitory role of LINC00472 in tumorigenesis was validated in vivo, and the LINC00472‐mediated miR‐23a‐3p/FOXO3/BID axis was also demonstrated in the nude mouse tumour formation model. The study substantiated the antitumour activity of LINC00472 in pancreatic cancer and proposed a regulatory axis in which LINC00472 competitively binds to miR‐23a‐3p to enhance the FOXO3 expression and promote BID expression. Consequently, these findings provide theoretical basis for developing potential targets for the treatment of pancreatic cancer.

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Section: Discussionsupporting

confidence: 91%

LINC00472 suppressed by ZEB1 regulates the miR‐23a‐3p/FOXO3/BID axis to inhibit the progression of pancreatic cancer

Wang

2021

J Cellular Molecular Medi

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“…As a transcriptional repressor, ZBTB16 has an important role in cell death, differentiation, and tumor progression. 25 Downregulation of ZBTB16 was observed in pancreatic cancer and prostate cancer, 26,27 and the high expression of ZBTB16 was associated with long-term survival in cancer patients. 28,29 In our study, ZBTB16 was reduced, and this reduction might be one of the possible factors associated with pLELC tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Molecular characteristics of primary pulmonary lymphoepithelioma-like carcinoma based on integrated genomic analyses

Chen

Dai

Zhou

et al. 2021

Sig Transduct Target Ther

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Primary pulmonary lymphoepithelioma-like carcinoma (pLELC) is a rare non-small cell lung cancer (NSCLC) subtype. Clinical features have been described in our previous report, but molecular characteristics remain unclear. Herein, pLELC genomic features were explored. Among 41,574 lung cancers, 128 pLELCs and 162 non-pLELC NSCLCs were enrolled. Programmed cell death ligand 1 (PD-L1) and protein 53 (p53) expression was detected in 47 surgically resected pLELC samples by immunohistochemical assays. Multiomics genomic analyses, including whole-genome sequencing (WGS), RNA whole-transcriptome sequencing (RNA-seq), and Epstein-Barr virus (EBV) integration analyses, were performed on eight frozen pLELC tissues and compared with 50 lung adenocarcinomas (LUADs) and 50 lung squamous cell carcinomas (LUSCs) from The Cancer Genome Atlas (TCGA) and another 26 EBV-positive nasopharynx cancers (EBV+-NPCs). Progression-free survival (PFS) and overall survival (OS) of pLELC patients were better than those of non-pLELC patients. High PD-L1 or p53 expression was associated with extended disease-free survival (DFS). pLELC had 14 frequently mutated genes (FMGs). Somatically mutated genes and enrichment of genetic lesions were found, which differed from observations in LUAD, LUSC, and EBV+-nasopharyngeal carcinoma (NPC). Three tumor-associated genes, zinc finger and BTB domain-containing 16 (ZBTB16), peroxisome proliferator activated receptor gamma (PPARG), and transforming growth factor beta receptor 2 (TGFBR2), were downregulated with copy number variation (CNV) loss. EBV was prone to integrating into intergenic and intronic regions with two upregulated miR-BamH1-A rightward transcripts (BARTs), BART5-3P and BART20-3P. Our findings reveal that pLELC has a distinct genomic signature. Three tumor-associated genes with CNV loss and two miR-BARTs might be involved in pLELC tumorigenesis.

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“…Akt phosphorylates FOXO3a at multiple sites and leads to its transportation out of the nucleus and retention in the cytoplasm (27,28). FOXO3a regulates the protein expression of PTEN, and expression of the PTEN/FOXO3a/PLZF signaling pathway is associated with tumor progression (29). Docetaxel has been shown to induce cancer cell apoptosis at least partly by enhancing FOXO3a activity and stimulating its nuclear translocation (30).…”

Section: Introductionmentioning

confidence: 99%

Combined Anti-Cancer Effects of Platycodin D and Sorafenib on Androgen-Independent and PTEN-Deficient Prostate Cancer

Song

Zhang

et al. 2021

Front. Oncol.

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Castration-resistant (androgen-independent) and PTEN-deficient prostate cancer is a challenge in clinical practice. Sorafenib has been recommended for the treatment of this type of cancer, but is associated with several adverse effects. Platycodin D (PD) is a triterpene saponin with demonstrated anti-cancer effects and a good safety profile. Previous studies have indicated that PC3 cells (PTEN -/-, AR -/-) are sensitive to PD, suggesting that it may also be a useful treatment for castration-resistance prostate cancer. We herein investigated the effects of combining PD with sorafenib to treat PTEN-deficient prostate cancer cells. Our data show that PD promotes sorafenib-induced apoptosis and cell cycle arrest in PC3 cells. Of interest, PD only promoted the anti-cancer effects of sorafenib in Akt-positive and PTEN-negative prostate cancer cells. Mechanistic studies revealed that PD promoted p-Akt ubiquitination by increasing the p-Akt level. PD also increased the protein and mRNA expression of FOXO3a, the downstream target of Akt. Meanwhile, PD promoted the activity of FOXO3a and increased the protein expression of Fasl, Bim and TRAIL. Interestingly, when FOXO3a expression was inhibited, the antitumor effects of both PD and sorafenib were individually inhibited, and the more potent effects of the combination treatment were inhibited. Thus, the combination of PD and sorafenib may exert potent anti-cancer effects specifically via FOXO3a. The use of Akt inhibitors or FOXO3a agonists, such as PD, may represent a promising approach for the treatment of androgen-independent and PTEN-deficient prostate cancer.

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Expression of the PTEN/FOXO3a/PLZF signalling pathway in pancreatic cancer and its significance in tumourigenesis and progression

Cited by 19 publications

References 36 publications

LINC00472 suppressed by ZEB1 regulates the miR‐23a‐3p/FOXO3/BID axis to inhibit the progression of pancreatic cancer

LINC00472 suppressed by ZEB1 regulates the miR‐23a‐3p/FOXO3/BID axis to inhibit the progression of pancreatic cancer

Molecular characteristics of primary pulmonary lymphoepithelioma-like carcinoma based on integrated genomic analyses

Combined Anti-Cancer Effects of Platycodin D and Sorafenib on Androgen-Independent and PTEN-Deficient Prostate Cancer

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