Targeting Jak/Stat pathway as a therapeutic strategy against SP/CD44+ tumorigenic cells in Akt/β-catenin-driven hepatocellular carcinoma

Toh, Tan Boon; Lim, Jackwee; Hooi, Lissa; Rashid, Masturah Bte Mohd Abdul; Chow, Edward Kai‐Hua

doi:10.1016/j.jhep.2019.08.035

Cited by 104 publications

(77 citation statements)

References 55 publications

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“…Inhibition of STAT3 via small molecule inhibitors significantly reduced the SP/CD44 + cells in vitro and diminished the tumor formation capacity in vivo. This demonstrates the potential of targeting STAT3 in controlling the population of cells containing stem cell-like properties in HCC [52]. Additionally, STAT3 phosphorylation and activation have also been reported to regulate the expression of other cancer stem cell markers in HCC, namely CD133 and NANOG [54,55].…”

Section: Stat3 In Cancer Stem Cellsmentioning

confidence: 69%

“…The activation of STAT3 has been demonstrated to correlate with cancer stem cell markers that confer stem cell-like properties to tumor cells. STAT3 activation has been shown to correlate with the self-renewing side population/CD44-positive (SP/CD44 + ) cells in HCC [52]. CD44 is traditionally reported to maintain cell populations with cancer stem cell-like properties in HCC [53].…”

Section: Stat3 In Cancer Stem Cellsmentioning

confidence: 99%

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JAK/STAT signaling in hepatocellular carcinoma

et al. 2020

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Liver cancer is the second most lethal cancer in the world with limited treatment options. Hepatocellular carcinoma (HCC), which accounts for more than 80% of all liver cancers, has had increasing global incidence over the past few years. There is an urgent need for novel and better therapeutic intervention for HCC patients. The JAK/STAT signaling pathway plays a multitude of important biological functions in both normal and malignant cells. In a subset of HCC, JAK/STAT signaling is aberrantly activated, leading to dysregulation of downstream target genes that controls survival, angiogenesis, stemness, immune surveillance, invasion and metastasis. In this review, we will focus on the role of JAK/STAT signaling in HCC and discuss the current clinical status of several JAK/STAT inhibitors.

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Section: Stat3 In Cancer Stem Cellsmentioning

confidence: 69%

Section: Stat3 In Cancer Stem Cellsmentioning

confidence: 99%

JAK/STAT signaling in hepatocellular carcinoma

et al. 2020

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“…Moreover, a high incidence of cancer, especially lymphoma, has been reported in subjects with primary immunodeficiency (20). Numerous studies have reported the association between JAK/STAT and various malignancies and inflammatory pathologies, suggesting that JAK-targeted drugs may be successful for the treatment of cancer and immune-mediated diseases (21)(22)(23)(24)(25)(26)(27). A previous study indicated that the downregulation of MYBL2 caused cell cycle arrest at the G 2 /M phase via the p53-p21-DREAM-CDE/CHR pathway (28).…”

Section: Discussionmentioning

confidence: 99%

Upregulation of MYBL2 independently predicts a poorer prognosis in patients with clear cell renal cell carcinoma

Sun

Lin

2020

Oncol Lett

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MYB protooncogene-like 2 (MYBL2) is a transcription factor that is upregulated and significantly associated with various human cancer types. However, the potential role of MYBL2 in clear cell renal cell carcinoma (ccRCC) is yet to be elucidated. Therefore, the expression and biological functions of MYBL2 in ccRCC were assessed in the current study using The Cancer Genome Atlas (TCGA). A Wilcoxon signed-rank test was performed to compare MYBL2 expression between ccRCC and normal tissues. Moreover, the association between MYBL2 expression and various clinicopathological factors was estimated using both the Wilcoxon signed-rank test and logistic regression. The differences in prognosis between patients with high-and low-MYBL2 expression were analyzed via the Kaplan-Meier method and Cox regression analysis. Finally, gene set enrichment analysis (GSEA) was performed to investigate the biofunctions of MYBL2 in ccRCC. It was revealed that MYBL2 was upregulated in ccRCC, and that the MYBL2 high-expression phenotype was significantly associated with sex, a high histological grade, an advanced clinical stage, tumor stage, lymph node metastasis, distant metastasis and poor overall survival (OS). It was also revealed, via the Cox regression analysis, that the upregulation of MYBL2 expression was able to independently predict a poor prognosis in patients with ccRCC. GSEA indicated that the intestinal immune network for IgA production, primary immunodeficiency, the janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, the cytosolic DNA-sensing pathway, the p53 signaling pathway and the chemokine signaling pathway were all enriched in the high-MYBL2 expression datasets. In conclusion, the present findings indicate that MYBL2 may be used as an independent prognostic factor in patients with ccRCC.

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“…Wnt/β-catenin signaling pathway as an evolutionarily conserved signaling pathway not just participates in embryogenesis, but also in cancer cell survival, invasion, migration and multidrug-chemoresistance [15,16]. P-glycoprotein refers to an ATP-binding Cassette (ABC) e ux transporter distributing on the cell membrane extensively.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-138-1-3p sensitizes sorafenib to hepatocellular carcinoma by targeting PAK5 mediated β-catenin/ABCB1 signaling pathway

Mou

Pan

et al. 2020

Preprint

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Background: Kinase inhibitor sorafenib is the first-line targeted drug for advanced hepatocellular carcinoma (HCC) patients. However, the appearance of anti-cancer agents’ resistance has limited its therapeutic effect. Methods: In this study, quantitative real-time PCR (qPCR) and Western Blot were utilized to detect the levels of PAK5 in HCC sorafenib-resistant cells and their parental cells. The biological functions of miR-138-1-3p and PAK5 in sorafenib-resistant cells and their parental cells were explored by cell viability assay, plate colony formation assay and flow cytometric analysis. The potential mechanisms of PAK5 were evaluated via co-immunoprecipitation (co-IP), immunofluorescence, dual luciferase reporter assay and chromatin immunoprecipitation (ChIP). The effects of miR-138-1-3p and PAK5 on HCC sorafenib chemoresistant characteristics were investigated by a xenotransplantation model. Results: We detected significant down-regulation of miR-138-1-3p and up-regulation of PAK5 in HCC sorafenib resistance cell lines. Mechanical studies revealed that miR-138-1-3p reduced the protein expression of PAK5 by directly targeting the 3′-UTR of PAK5 mRNA. In addition, we verified that PAK5 elevated the phosphorylation and nuclear translocation of β-catenin that enhanced the transcriptional activity of multidrug resistance protein ABCB1. Conclusions: PAK5 contributed to the sorafenib chemoresistant characteristics of HCC by activity β-catenin/ABCB1 signaling pathway. Our findings identified the correlation between miR-138-1-3p and PAK5 and the molecular mechanisms of PAK5-mediated HCC sorafenib resistance, which provided a potential therapeutic target for advanced HCC patients.

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Targeting Jak/Stat pathway as a therapeutic strategy against SP/CD44+ tumorigenic cells in Akt/β-catenin-driven hepatocellular carcinoma

Cited by 104 publications

References 55 publications

JAK/STAT signaling in hepatocellular carcinoma

JAK/STAT signaling in hepatocellular carcinoma

Upregulation of MYBL2 independently predicts a poorer prognosis in patients with clear cell renal cell carcinoma

MicroRNA-138-1-3p sensitizes sorafenib to hepatocellular carcinoma by targeting PAK5 mediated β-catenin/ABCB1 signaling pathway

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