CD44 standard isoform is involved in maintenance of cancer stem cells of a hepatocellular carcinoma cell line

Asai, Ryoma; Tsuchiya, Hiroyuki; Amisaki, Masataka; Makimoto, Kazuki; Takenaga, Ai; Sakabe, Tomohiko; Hoi, Shotaro; Koyama, Shigemi; Shiota, Goshi

doi:10.1002/cam4.1968

Cited by 51 publications

(44 citation statements)

References 51 publications

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“…Our previous study suggested that the expression of CD44 standard isoform (CD44s) in HCC tissues is associated with poor prognosis [17]. We also demonstrated that CD44s plays an important role in the maintenance of CSC properties of a human HCC cell line using CD44-knockout (CD44-KO) cells [18]. These findings suggest that CD44 is a promising target for treating HCC.…”

Section: Introductionmentioning

confidence: 85%

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NEAT1 is Required for the Expression of the Liver Cancer Stem Cell Marker CD44

Koyama

Tsuchiya

Amisaki

et al. 2020

IJMS

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CD44, a cancer stem cell (CSC) marker, is required for maintaining CSC properties in hepatocellular carcinoma (HCC). Nuclear enriched abundant transcript 1 (NEAT1), a long noncoding RNA (lncRNA), is an oncogenic driver in HCC. In the present study, we investigated the significance of the NEAT1 gene in association with CD44 expression in liver CSCs of human HCC cell lines. The CSC properties were evaluated by spheroid culture, CSC marker expression, and sensitivity to anti-cancer drugs. The expression of both NEAT1 variant 1 (NEAT1v1) and variant 2 (NEAT1v2) as well as CD44 was significantly increased in the spheroid culture, compared with that in monolayer culture. Overexpression of Neat1v1, but not Neat1v2, enhanced the CSC properties, while knockout of the NEAT1 gene suppressed them. CD44 expression was increased by the overexpression of Neat1v1 and abrogated by NEAT1 knockout. The overexpression of NEAT1v1 restored the CSC properties and CD44 expression in NEAT1-knockout cells. NEAT1v1 expression in HCC tissues was correlated with poor prognosis and CD44 expression. These results suggest that NEAT1v1 is required for CD44 expression. To our surprise, NEAT1v1 also restored the CSC properties even in CD44-deficient cells, suggesting that NEAT1v1 maintains the properties of CSCs in a CD44-independent manner.

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Section: Introductionmentioning

confidence: 85%

“…We previously reported that CD44 maintains CSC properties possibly through NOTCH3 in HCC cells [18]. Because CD44 expression is induced by hNEAT1v1, it was investigated whether hNEAT1v1 regulates CSC properties via CD44.…”

Section: Rescue Of Cd44-ko Cells By Neat1v1mentioning

confidence: 99%

NEAT1 is Required for the Expression of the Liver Cancer Stem Cell Marker CD44

Koyama

Tsuchiya

Amisaki

et al. 2020

IJMS

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“…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]. Inhibition of STAT3 via small molecule inhibitors significantly reduced the SP/CD44 + cells in vitro and diminished the tumor formation capacity in vivo.…”

Section: Stat3 In Cancer Stem Cellsmentioning

confidence: 99%

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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“…TICs are mainly identified through tumor formation in vivo, sphere formation in vitro, and specific cell markers. In HCC, CD44 is TIC marker most associated with the epithelial-mesenchymal transition (EMT), drug resistance and tumor formation in immunodeficient mice [9][10][11], suggesting that CD44 expression might be a crucial sign to guide clinical treatment. In addition, various stemness-related signals, such as Notch, Hippo, Wnt and Hedgehog signaling, are usually aberrantly activated in TICs, and drug resistance can be overcome by blocking these signals [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Hedgehog signaling promotes sorafenib resistance in hepatocellular carcinoma patient-derived organoids

Wang

Xun

et al. 2020

J Exp Clin Cancer Res

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Background: The mechanism underlying sorafenib resistance in hepatocellular carcinoma (HCC) remains unclear. Accumulating evidence suggests that tumor-initiating cells (TICs) are a pivotal driving force. Both CD44 and Hedgehog signaling play crucial roles in TIC properties in HCC. In this study, we explored the roles of CD44 and Hedgehog signaling in sorafenib resistance and evaluated the therapeutic effect of cotreatment with sorafenib and Hedgehog signaling inhibitors in HCC patient-derived organoid (PDO) models to improve treatment efficacy. Methods: We collected HCC specimens to establish PDO models. Cell viability and malignant transformation properties were investigated after treatment with different TIC-related inhibitors alone or in combination with sorafenib to evaluate the therapeutic effect in PDOs and cell lines by in vitro and in vivo experiments. Expression levels of Hedgehog signaling proteins and CD44 were monitored to reveal potential relationships. Results: We demonstrated that our HCC PDO models strongly maintained the histological features of the corresponding tumors and responded to drug treatment. Furthermore, CD44-positive HCC PDOs were obviously resistant to sorafenib, and sorafenib increased CD44 levels. A drug screen showed that compared with Notch, Hippo and Wnt signaling inhibitors, a Hedgehog signaling inhibitor (GANT61) potently suppressed HCC PDO cell viability. In addition, there was a highly synergistic effect in vitro and in vivo on the suppression of cell viability and malignant properties when sorafenib and GANT61 were added to CD44-positive HCC PDOs and cell lines, respectively. Furthermore, the upregulation of CD44 and Hedgehog signaling induced by sorafenib was reversed by GANT61. Conclusions: GANT61 significantly suppressed Hedgehog signaling to reverse sorafenib resistance in CD44-positive HCC. The combination of sorafenib and Hedgehog signaling inhibitors might be effective in HCC patients with high CD44 levels as a personalized-medicine approach.

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CD44 standard isoform is involved in maintenance of cancer stem cells of a hepatocellular carcinoma cell line

Cited by 51 publications

References 51 publications

NEAT1 is Required for the Expression of the Liver Cancer Stem Cell Marker CD44

NEAT1 is Required for the Expression of the Liver Cancer Stem Cell Marker CD44

JAK/STAT signaling in hepatocellular carcinoma

Hedgehog signaling promotes sorafenib resistance in hepatocellular carcinoma patient-derived organoids

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