Enhanced Hsa-miR-181d/p-STAT3 and Hsa-miR-181d/p-STAT5A Ratios Mediate the Anticancer Effect of Garcinol in STAT3/5A-Addicted Glioblastoma
Authors: Iat-Hang Fong
I-Hung Kan
Peter Mingjui Lee
Chi-Tai Yeh
Chien-Min Lin
Heng-Wei Liu
Yu-Kai Su
Oluwaseun Adebayo Bamodu
Ming-Hsien Chien
Journal: Cancers (2019)
Discipline: CLINICAL MEDICINE
Keywords: GBM; STAT3; STAT5A; glioblastoma; glioma
Affiliations: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City 11031, Taiwan., Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei City 11031, Taiwan., Division of Neurosurgery, Department of Surgery, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan., Taipei Neuroscience Institute, Taipei Medical University, Taipei 11031, Taiwan., Department of Clinical Oncology, College of Medicine, California North State University, Elk Grove, CA 95757, USA., Department of Hematology and Oncology, Cancer Center, Taipei Medical University-Shuang Ho Hospital, New Taipei City 235, Taiwan., Department of Medical Research and Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 235, Taiwan., Department of Medical Laboratory Science and Biotechnology, Yuanpei University of Medical Technology, Hsinchu City 30015, Taiwan.

Abstract:  Background: Glioblastoma (GBM), a malignant grade IV tumor, is the most malignant brain tumor due to its hyper-proliferative and apoptosis-evading characteristics. The signal transducer and activators of transcription (STAT) family genes, including STAT3 and STAT5A, have been indicated to play important roles in GBM progression. Increasing number of reports suggest that garcinol, a polyisoprenylated benzophenone and major bioactive component of Garcinia indica contains potent anti-cancer activities. Material and methods: The present study investigated the anti-GBM effects of garcinol, focusing on the STAT3/STAT5A activation, using a combination of bioinformatics, in vitro, and ex vivo assays. Results: Our bioinformatics analysis of The Cancer Genome Atlas (TCGA)-GBM cohort (n = 173) showed that STAT3 and STAT5A are preferentially elevated in primary and recurrent GBM, compared to non-tumor brain tissues, and is significantly correlated with reduced overall survival. In support, our immunohistochemical staining of a GBM cohort (n = 45) showed an estimated 5.3-fold (p &lt; 0.001) elevation in STAT3 and STAT5A protein expression in primary and recurrent GBM versus the non-tumor group. In vitro, garcinol treatment significantly suppressed the proliferative, invasive, and migratory potential of U87MG or GBM8401 cells, dose-dependently. In addition, garcinol anticancer effect significantly attenuated the GBM stem cell-like phenotypes, as reflected by diminished ability of U87MG or GBM8401 to form colonies and tumorspheres and suppressed expression of OCT4 and SOX2. Furthermore, analysis on GBM transcriptome revealed an inverse correlation between the level of STAT3/5A and hsa-miR-181d. Garcinol-mediated anti-GBM effects were associated with an increased hsa-miR-181d/STAT3 and hsa-miR-181d/5A ratio. The results were further verified in vivo using U87MG mouse xenograft model where administration of garcinol significantly inhibited tumor growth. Conclusions: We present evidence of anti-GBM efficacy of garcinol mediated by enhancing the hsa-miR-181d/STAT3 and hsa-miR-181d/5A ratios in GBM cells. Our findings suggest a potential new therapeutic agent for combating aggressive GBM. 

Retracted: No

PubPeer comments:
 Very unusual similar patterns appear in Fig. 2E. ![file] The authors should provide the original cytometry files. I will also be appreciated if the authors can provide high resolutions of Fig. 2F as we can t see the scatching assay very well. , 
 October 1, 2020 The authors wish to make the following corrections to this paper [1]: After the publication of this work, we were notified of the mistakes in Figure 2E and Section 3.2, which have now been updated in this correction. The original Figure 2E and legend of Figure 2E (omitted here) are as below: In addition, the authors reported errors in Section 3.2 when analyzing the original data in Figure 2E. Thus, the authors wish to replace the following sentence in Section 3.2: u201cu2026and 7.97% or 14.11% apoptosis of the U87MG cells (Figure 2E), indicating that the garcinol-induced cell death was apoptotic and caspase-dependent.u201d with: u201cu2026and 7.97% or 12.99% apoptosis of the U87MG cells (Figure 2E), indicating that the garcinol-induced cell death was apoptotic and caspase-dependent.u201d The corrections made in this erratum do not affect the original conclusions. The authors would like to apologize for any inconvenience caused to the readers by these changes. , 
 Correction: Liu, H.W.; et al. Enhanced Hsa-miR-181d p-STAT3 and Hsa-miR-181d p-STAT5A Ratios Mediate the Anticancer Effect of Garcinol in STAT3 5A-Addicted Glioblastoma. Cancers 2019, 11, 1888. Liu HW, Lee PM, Bamodu OA, Su YK, Fong IH, Yeh CT, Chien MH, Kan IH, Lin CM. Cancers (Basel). 2020 Oct 1;12(10):2846. doi: 10.3390 cancers12102846. , 
 Please see our Correction: Liu, H.W.; et al. Enhanced Hsa-miR-181d p-STAT3 and Hsa-miR-181d p-STAT5A Ratios Mediate the Anticancer Effect of Garcinol in STAT3 5A-Addicted Glioblastoma. Cancers 2019, 11, 1888. Liu HW, Lee PM, Bamodu OA, Su YK, Fong IH, Yeh CT, Chien MH, Kan IH, Lin CM. Cancers (Basel). 2020 Oct 1;12(10):2846. doi: 10.3390 cancers12102846. ,