Enhanced Hsa-mir-181d/p-STAT3 and Hsa-miR-181d/p-STAT5A ratios mediate the anticancer effect of garcinol in STAT3/5A-addicted glioblastoma

Heng Wei Liu, Peter Mingjui Lee, Oluwaseun Adebayo Bamodu, Yu Kai Su, Iat Hang Fong, Chi Tai Yeh, Ming Hsien Chien, I. Hung Kan, Chien Min Lin

Research output: Contribution to journalArticle

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 < 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.

Original languageEnglish
Article number1888
JournalCancers
Volume11
Issue number12
DOIs
Publication statusPublished - Dec 2019

Fingerprint

Glioblastoma
Computational Biology
garcinol
Neoplasms
Garcinia
STAT3 Transcription Factor
Atlases
Transducers
Transcriptome
Heterografts
Brain Neoplasms
Stem Cells
Genome
Apoptosis
Staining and Labeling

Keywords

  • GBM
  • Glioblastoma
  • Glioma
  • Hsa-miR-181d
  • MicroRNA
  • STAT3
  • STAT5A

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Enhanced Hsa-mir-181d/p-STAT3 and Hsa-miR-181d/p-STAT5A ratios mediate the anticancer effect of garcinol in STAT3/5A-addicted glioblastoma. / Liu, Heng Wei; Lee, Peter Mingjui; Bamodu, Oluwaseun Adebayo; Su, Yu Kai; Fong, Iat Hang; Yeh, Chi Tai; Chien, Ming Hsien; Kan, I. Hung; Lin, Chien Min.

In: Cancers, Vol. 11, No. 12, 1888, 12.2019.

Research output: Contribution to journalArticle

Liu, Heng Wei ; Lee, Peter Mingjui ; Bamodu, Oluwaseun Adebayo ; Su, Yu Kai ; Fong, Iat Hang ; Yeh, Chi Tai ; Chien, Ming Hsien ; Kan, I. Hung ; Lin, Chien Min. / Enhanced Hsa-mir-181d/p-STAT3 and Hsa-miR-181d/p-STAT5A ratios mediate the anticancer effect of garcinol in STAT3/5A-addicted glioblastoma. In: Cancers. 2019 ; Vol. 11, No. 12.
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title = "Enhanced Hsa-mir-181d/p-STAT3 and Hsa-miR-181d/p-STAT5A ratios mediate the anticancer effect of garcinol in STAT3/5A-addicted glioblastoma",
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 < 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.",
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author = "Liu, {Heng Wei} and Lee, {Peter Mingjui} and Bamodu, {Oluwaseun Adebayo} and Su, {Yu Kai} and Fong, {Iat Hang} and Yeh, {Chi Tai} and Chien, {Ming Hsien} and Kan, {I. Hung} and Lin, {Chien Min}",
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T1 - Enhanced Hsa-mir-181d/p-STAT3 and Hsa-miR-181d/p-STAT5A ratios mediate the anticancer effect of garcinol in STAT3/5A-addicted glioblastoma

AU - Liu, Heng Wei

AU - Lee, Peter Mingjui

AU - Bamodu, Oluwaseun Adebayo

AU - Su, Yu Kai

AU - Fong, Iat Hang

AU - Yeh, Chi Tai

AU - Chien, Ming Hsien

AU - Kan, I. Hung

AU - Lin, Chien Min

PY - 2019/12

Y1 - 2019/12

N2 - 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 < 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.

AB - 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 < 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.

KW - GBM

KW - Glioblastoma

KW - Glioma

KW - Hsa-miR-181d

KW - MicroRNA

KW - STAT3

KW - STAT5A

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