Transcription factor PAX6 as a novel prognostic factor and putative tumour suppressor in non-small cell lung cancer

Kiselev, Yury; Andersen, Sigve; Johannessen, Charles; Fjukstad, Bjørn; Olsen, Karina Standahl; Stenvold, Helge; Al-Saad, Samer; Dønnem, Tom; Richardsen, Elin; Bremnes, Roy M.; Busund, Lill-Tove

doi:10.1038/s41598-018-23417-z

Cited by 13 publications

(10 citation statements)

References 59 publications

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“…14,23 However, a previous study reported conflicting results, suggesting that PAX6 is a positive prognostic marker in NSCLC in node-positive patients. 40 These differences could be attributed to a lack of sufficient data and clarity regarding the underlying mechanism of the role of PAX6 in this disease. The current study showed that higher PAX6 expression significantly correlated with reduced duration of OS in lung cancer.…”

Section: Discussionmentioning

confidence: 99%

The PAX6-ZEB2 axis promotes metastasis and cisplatin resistance in non-small cell lung cancer through PI3K/AKT signaling

Zhang

Liu

et al. 2019

Cell Death Dis

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Paired-box 6 (PAX6) is an important transcription factor required for the function of human neuroectodermal epithelial tissues. Previous studies have suggested that it is also expressed in several types of tumors and has an oncogenic role. However, little is known about its role in non-small cell lung cancer (NSCLC). Here, we found that PAX6 expression levels were upregulated in human lung cancer tissues and correlated with poor clinical outcomes. PAX6 overexpression significantly promoted NSCLC epithelial-to-mesenchymal transition (EMT) and metastasis, whereas its knockdown inhibited these processes. PAX6 is commonly correlated with EMT-mediated stem cell transformation, thereby inducing cisplatin resistance. Using the RT 2 Profiler PCR Array, we found that WNT5A , EGFR , and ZEB2 were differentially regulated in response to PAX6 modulation. In addition, PAX6 directly bound to the promoter region of ZEB2 . ZEB2 knockdown significantly reduced the expression and function of PAX6. ZEB2 was upregulated upon PAX6 overexpression and downregulated upon PAX6 knockdown, whereas E-cadherin expression negatively correlated with PAX6 levels. Moreover, p-PI3K and p-AKT were significantly enhanced by PAX6, which was reversed by the addition of the PI3K-AKT inhibitor, LY294002. These data suggest that PAX6 can mediate E-cadherin downregulation through the PI3K/AKT signaling pathway by directly binding the promoter region of ZEB2 , thereby mediating cell migration, stem cell transformation, and cisplatin resistance; and ultimately, affecting survival in NSCLC patients.

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Section: Discussionmentioning

confidence: 99%

The PAX6-ZEB2 axis promotes metastasis and cisplatin resistance in non-small cell lung cancer through PI3K/AKT signaling

Zhang

Liu

et al. 2019

Cell Death Dis

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“…The mechanism of action of PAX6 as a tumor suppressor has been shown in retinoblastoma, prostate cancer, and glioblastoma cell lines. On the other hand, some oncogenic properties of PAX6 were found in colorectal adenocarcinoma, retinoblastoma, and breast tumor cell lines ( Kiselev et al, 2018 ). In the miR-383/PAX6 pathway, downregulation of miR-383 together with the upregulation of PAX6 was found in CRC tissues and cells.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-383: A tumor suppressor miRNA in human cancer

Jafarzadeh

Noori

Sarrafzadeh

et al. 2022

Front. Cell Dev. Biol.

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Downregulated expression of anti-tumor miR-383 has been found in many kinds of cancer. MiR-383 family members can directly target the 3′-untranslated region (3′-UTR) of the mRNA of some pro-tumor genes to attenuate several cancer-related processes, including cell proliferation, invasion, migration, angiogenesis, immunosuppression, epithelial-mesenchymal transition, glycolysis, chemoresistance, and the development of cancer stem cells, whilst promoting apoptosis. Functionally, miR-383 operates as a tumor inhibitor miRNA in many types of cancer, including breast cancer, hepatocellular carcinoma, gastric cancer, pancreatic cancer, colorectal cancer, esophageal cancer, lung cancer, head and neck cancer, glioma, medulloblastoma, melanoma, prostate cancer, cervical cancer, oral squamous cell carcinoma, thyroid cancer, and B-cell lymphoma. Both pro-tumor and anti-tumor effects have been attributed to miR-383 in ovarian cancer. However, only the pro-tumor effects of miR-383 were reported in cholangiocarcinoma. The restoration of miR-383 expression could be considered a possible treatment for cancer. This review discusses the anti-tumor effects of miR-383 in human cancers, emphasizing their downstream target genes and potential treatment approaches.

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“…Similarly, Luo et al had suggested that miR-7 negatively regulates PAX6 protein levels, which can promote the proliferation and invasion of NSCLC cells via activation of the ERK and MAPK signaling pathways [16]. Kiselev et al also showed that the transcription factor PAX6 was a novel prognostic factor and putative tumor suppressor in non-small cell lung cancer [17]. Pax6 also interacts with the Smad3 MH1 domain, and Pax6/Smad3 interactions appear to be necessary for TGF-β signaling [18].…”

Section: Introductionmentioning

confidence: 99%

Investigating the mechanism by which SMAD3 induces PAX6 transcription to promote the development of non-small cell lung cancer

Zhang

et al. 2018

Respir Res

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BackgroundThis study investigated the function of SMAD3 (SMAD family member 3) in regulating PAX6 (paired box 6) in non-small cell lung cancer.MethodsFirst, qRT-PCR was employed to detect SMAD3 expression in cancer tissues along with normal tissues and four cell lines, including BEAS-2B, H125, HCC827 and A549 cells. SMAD3 was knocked down by small interference RNA (siRNA), and then its expression was determined via qRT-PCR and Western blot analysis. The correlation between SMAD3 and PAX6 was determined by double luciferase reporter experiments and chromatin immunoprecipitation (ChIP) assay. Cell viability was evaluated by CCK-8 and colony forming assays, while cell migration and invasion were detected by Transwell analysis.ResultsSMAD3 and PAX6 were upregulated in lung cancer tissues and cancer cells. Knocking down SMAD3 and PAX6 by transfection with siRNAs specifically suppressed the expression of SMAD3 and PAX6 mRNA and protein levels. SMAD3 could promote PAX6 transcriptional activity by binding to its promoter. Reduced expression of SMAD3 led to the downregulation of PAX6 mRNA and protein levels along with decreased cell migration, invasion, proliferation and viability in A549 and HCC827 cells. PAX6 overexpression altered the si-SMAD3-induced inhibition of cell migration, invasion, proliferation and viability in A549 and HCC827 cells. Additionally, PAX6 knockdown alone also repressed the cell migration, invasion, proliferation and viability of the cell lines.ConclusionsSMAD3 promotes the progression of non-small cell lung cancer by upregulating PAX6 expression.Electronic supplementary materialThe online version of this article (10.1186/s12931-018-0948-z) contains supplementary material, which is available to authorized users.

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Transcription factor PAX6 as a novel prognostic factor and putative tumour suppressor in non-small cell lung cancer

Cited by 13 publications

References 59 publications

The PAX6-ZEB2 axis promotes metastasis and cisplatin resistance in non-small cell lung cancer through PI3K/AKT signaling

The PAX6-ZEB2 axis promotes metastasis and cisplatin resistance in non-small cell lung cancer through PI3K/AKT signaling

MicroRNA-383: A tumor suppressor miRNA in human cancer

Investigating the mechanism by which SMAD3 induces PAX6 transcription to promote the development of non-small cell lung cancer

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