LSD1 Stimulates Cancer-Associated Fibroblasts to Drive Notch3-Dependent Self-Renewal of Liver Cancer Stem–like Cells

<p>The present study demonstrates the effects of triptolide, one of the constituents from Tripterygium wilfordii, on the self‑renewal capacity of human hepatocellular carcinoma. The investigation revealed that triptolide markedly prevented the proliferation of liver cancer stem cells (LCSCs). For the LCSCs the minimum inhibitory concentration of triptolide was 0.6 μM. There was a significant and obvious decrease in the capacity of LCSCs to form self-sphere. Furthermore, triptolide reduced the sphere-forming capacity of LCSCs along with inhibition of β‑catenin expression. However, the exposure of triptolide-treated cells to lithium chloride, an activator the Wnt/β-catenin signaling pathway, reversed the triptolide-induced inhibition of β-catenin expression and inhibited the self-renewal capacity. Therefore, triptolide effectively eradicates LCSCs through the inhibition of β-catenin protein and may act as a novel agent for the treatment of hepatocellular carcinoma.</p><p> </p>

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MicroRNA-449a maintains self-renewal in liver cancer stem-like cells by targeting Tcf3

Oncotarget ◽

10.18632/oncotarget.22705 ◽

2017 ◽

Vol 8 (66) ◽

pp. 110187-110200 ◽

Cited By ~ 5

Author(s):

Qianzhen Zhang ◽

Zhi Yang ◽

Juanjuan Shan ◽

Limei Liu ◽

Chungang Liu ◽

...

Keyword(s):

Liver Cancer ◽

Self Renewal

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MicroRNA-28-5p Regulates Liver Cancer Stem Cell Expansion via IGF-1 Pathway

Stem Cells International ◽

10.1155/2019/8734362 ◽

2019 ◽

Vol 2019 ◽

pp. 1-16 ◽

Cited By ~ 2

Author(s):

Qing Xia ◽

Tao Han ◽

Pinghua Yang ◽

Ruoyu Wang ◽

Hengyu Li ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Liver Cancer ◽

Critical Role ◽

Self Renewal ◽

Sorafenib Treatment ◽

The Impact

Background. MicroRNAs (miRNAs) play a critical role in the regulation of cancer stem cells (CSCs). However, the role of miRNAs in liver CSCs has not been fully elucidated. Methods. Real-time PCR was used to detect the expression of miR-miR-28-5p in liver cancer stem cells (CSCs). The impact of miR-28-5p on liver CSC expansion was investigated both in vivo and in vitro. The correlation between miR-28-5p expression and sorafenib benefits in HCC was further evaluated in patient-derived xenografts (PDXs). Results. Our data showed that miR-28-5p was downregulated in sorted EpCAM- and CD24-positive liver CSCs. Biofunctional investigations revealed that knockdown miR-28-5p promoted liver CSC self-renewal and tumorigenesis. Consistently, miR-28-5p overexpression inhibited liver CSC’s self-renewal and tumorigenesis. Mechanistically, we found that insulin-like growth factor-1 (IGF-1) was a direct target of miR-28-5p in liver CSCs, and the effects of miR-28-5p on liver CSC’s self-renewal and tumorigenesis were dependent on IGF-1. The correlation between miR-28-5p and IGF-1 was confirmed in human HCC tissues. Furthermore, the miR-28-5p knockdown HCC cells were more sensitive to sorafenib treatment. Analysis of patient-derived xenografts (PDXs) further demonstrated that the miR-28-5p may predict sorafenib benefits in HCC patients. Conclusion. Our findings revealed the crucial role of the miR-28-5p in liver CSC expansion and sorafenib response, rendering miR-28-5p an optimal therapeutic target for HCC.

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Twist2 promotes self-renewal of liver cancer stem-like cells by regulating CD24

Carcinogenesis ◽

10.1093/carcin/bgt364 ◽

2013 ◽

Vol 35 (3) ◽

pp. 537-545 ◽

Cited By ~ 43

Author(s):

Allan Yi Liu ◽

Yao Cai ◽

Yubin Mao ◽

Yancheng Lin ◽

Hong Zheng ◽

...

Keyword(s):

Liver Cancer ◽

Self Renewal

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Histone demethylase JMJD2D promotes the self-renewal of liver cancer stem-like cells by enhancing EpCAM and Sox9 expression

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.015335 ◽

2020 ◽

pp. jbc.RA120.015335

Author(s):

Yuan Deng ◽

Ming Li ◽

Minghui Zhuo ◽

Peng Guo ◽

Qiang Chen ◽

...

Keyword(s):

Liver Cancer ◽

Cancer Progression ◽

Liver Tumors ◽

The Self ◽

High Rate ◽

Sox9 Expression ◽

Self Renewal ◽

Lysine Demethylase

Cancer stem-like cells (CSCs) contribute to the high rate of tumor heterogeneity, metastasis, therapeutic resistance, and recurrence. Histone lysine demethylase 4D (KDM4D or JMJD2D) is highly expressed in colon and liver tumors, where it promotes cancer progression; however, the role of JMJD2D in CSCs remains unclear. Here, we show that JMJD2D expression was increased in liver cancer stem-like cells (LCSCs); downregulation of JMJD2D inhibited the self-renewal of LCSCs in vitro and in vivo and inhibited the lung metastasis of LCSCs by reducing the survival and the early lung seeding of circulating LCSCs. Mechanistically, JMJD2D promoted LCSC self-renewal by enhancing the expression of CSC markers EpCAM and Sox9; JMJD2D reduced H3K9me3 levels on the promoters of EpCAM and Sox9 to enhance their transcription via interaction with β-catenin/TCF4 and Notch1 intracellular domain, respectively. Restoration of EpCAM and Sox9 expression in JMJD2D-knockdown liver cancer cells rescued the self-renewal of LCSCs. Pharmacological inhibition of JMJD2D using 5-c-8HQ reduced the self-renewal of LCSCs and liver cancer progression. Collectively, our findings suggest that JMJD2D promotes LCSC self-renewal by enhancing EpCAM and Sox9 expression via Wnt/β-catenin and Notch signaling pathways and is a potential therapeutic target for liver cancer.

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MRC-5 Cancer-associated Fibroblasts Influence Production of Cancer Stem Cell Markers and Inflammation-associated Cell Surface Molecules, in Liver Cancer Cell Lines

International Journal of Medical Sciences ◽

10.7150/ijms.34758 ◽

2019 ◽

Vol 16 (8) ◽

pp. 1157-1170

Author(s):

Song-Ming Ding ◽

Jian-Fang Lu ◽

Muhammad Ibrahim Alhadi Edoo ◽

Lin Zhou ◽

Hai-Yang Xie ◽

...

Keyword(s):

Stem Cell ◽

Liver Cancer ◽

Cell Surface ◽

Cancer Stem Cell ◽

Stem Cell Markers ◽

Cancer Associated Fibroblasts ◽

Cell Surface Molecules ◽

Liver Cancer Cell ◽

Cancer Stem Cell Markers ◽

Surface Molecules

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Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A

Journal of Experimental Medicine ◽

10.1084/jem.20131195 ◽

2013 ◽

Vol 210 (13) ◽

pp. 2851-2872 ◽

Cited By ~ 165

Author(s):

Fiorenza Lotti ◽

Awad M. Jarrar ◽

Rish K. Pai ◽

Masahiro Hitomi ◽

Justin Lathia ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Microenvironment ◽

Cellular Heterogeneity ◽

Cancer Therapies ◽

Cancer Associated Fibroblasts ◽

Self Renewal ◽

Cytokines And Chemokines ◽

Response To Chemotherapy ◽

Cytotoxic Treatment

Many solid cancers display cellular hierarchies with self-renewing, tumorigenic stemlike cells, or cancer-initiating cells (CICs) at the apex. Whereas CICs often exhibit relative resistance to conventional cancer therapies, they also receive critical maintenance cues from supportive stromal elements that also respond to cytotoxic therapies. To interrogate the interplay between chemotherapy and CICs, we investigated cellular heterogeneity in human colorectal cancers. Colorectal CICs were resistant to conventional chemotherapy in cell-autonomous assays, but CIC chemoresistance was also increased by cancer-associated fibroblasts (CAFs). Comparative analysis of matched colorectal cancer specimens from patients before and after cytotoxic treatment revealed a significant increase in CAFs. Chemotherapy-treated human CAFs promoted CIC self-renewal and in vivo tumor growth associated with increased secretion of specific cytokines and chemokines, including interleukin-17A (IL-17A). Exogenous IL-17A increased CIC self-renewal and invasion, and targeting IL-17A signaling impaired CIC growth. Notably, IL-17A was overexpressed by colorectal CAFs in response to chemotherapy with expression validated directly in patient-derived specimens without culture. These data suggest that chemotherapy induces remodeling of the tumor microenvironment to support the tumor cellular hierarchy through secreted factors. Incorporating simultaneous disruption of CIC mechanisms and interplay with the tumor microenvironment could optimize therapeutic targeting of cancer.

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