CD44s is a crucial ATG7 downstream regulator for stem-like property, invasion, and lung metastasis of human bladder cancer (BC) cells

Zhu, Junlan; Huang, Grace; Hua, Xiaohui; Li, Yang; Huang, Yan; Che, Xun; Tian, Zhongxian; Liufu, Huating; Huang, Chao; Li, Jingxia; Xu, Jiheng; Dai, Wei; Huang, Haishan

doi:10.1038/s41388-018-0664-7

Cited by 41 publications

(38 citation statements)

References 70 publications

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“…It was reported that the deubiquitylation of CD44s protein by USP28 is required for maintaining the invasive and metastatic phenotypes of CSCs in human bladder cancer [43]. In HCC, c-MYC requires USP28 for its protein stabilization [44], implying that USP28 may also function in liver CSCs. However, NEAT1v1 maintains CSCs properties in a CD44-independent manner, suggesting that NEAT1v1 activates pathways other than USP28.…”

Section: Discussionmentioning

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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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: Discussionmentioning

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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“…It has been reported that PD-L1 expression levels are correlated with the response to PD-1-PD-L1 blockade in tumor cells [29,30]. Our previous studies have discovered that ATG7 overexpressed plays a critical role in cell invasion, growth and sphere formation of human BC cells [19,20].…”

Section: Resultsmentioning

confidence: 99%

“…The overexpression of ATG7 promotes human BC cells abnormal growth behavior both in vitro and in vivo [19]. Moreover, the TET1/USP28/CD44/RhoGDIβ pathway has been demonstrated to be critical for the oncogenic role of ATG7 [20]. Here, we further discovered another important ATG7 downstream mediator PD-L1, which exerted its oncogenic role in stem-like property, tumorigenesis, and invasion of human BC cells.…”

Section: Introductionmentioning

confidence: 85%

A Feedback Loop Formed by ATG7/Autophagy, FOXO3a/miR-145 and PD-L1 Regulates Stem-like Properties and Invasion in Human Bladder Cancer

Zhu

Luo

et al. 2019

Cancers

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Programmed cell death protein 1 (PD-1) and its ligand PD-L1 blockade have been identified to target immune checkpoints to treat human cancers with durable clinical benefit. Several studies reveal that the response to PD-1-PD-L1 blockade might correlate with PD-L1 expression levels in tumor cells. However, the mechanistic pathways that regulate PD-L1 protein expression are not understood. Here, we reported that PD-L1 protein is regulated by ATG7-autophagy with an ATG7-initiated positive feedback loop in bladder cancer (BC). Mechanistic studies revealed that ATG7 overexpression elevates PD-L1 protein level mainly through promoting autophagy-mediated degradation of FOXO3a, thereby inhibiting its initiated miR-145 transcription. The lower expression of miR-145 increases pd-l1 mRNA stability due to the reduction of its direct binding to 3′-UTR of pd-l1 mRNA, in turn leading to increasing in pd-l1 mRNA stability and expression, and finally enhancing stem-like property and invasion of BC cells. Notably, overexpression of PD-L1 in ATG7 knockdown cells can reverse the defect of autophagy activation, FOXO3A degradation, and miR-145 transcription attenuation. Collectively, our results revealed a positive feedback loop to promoting PD-L1 expression in human BC cells. Our study uncovers a novel molecular mechanism for regulating pd-l1 mRNA stability and expression via ATG7/autophagy/FOXO3A/miR-145 axis and reveals the potential for using combination treatment with autophagy inhibitors and PD-1/PD-L1 immune checkpoint blockade to enhance therapeutic efficacy for human BCs.

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“…Since different CD44 splicing variants may display different functions in breast cancer [12,15,16], we previously examined the expression of CD44 splice variants in breast cancer cell lines, MDA-MB-231 and MDA-MB-435, as well as primary breast cancer, and found that CD44 splicing variants were heterogeneously expressed and CD44s expression was higher in breast cancer cell lines and tissues, which correlated with a higher histology grade [54]. In this study, high level of CD44s mRNA was detected in CD44 + /CD24 − breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…CD44 + /CD24 − has been widely used as a breast cancer stem cell (BCSC) biomarker [5][6][7][8]. However, whether CD44 is a critically functional molecule in maintaining the characteristics of BCSCs remains controversial [9][10][11][12]. This has limited the development of new therapeutic strategies for breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Effect of CD44 knockdown on the biological characteristics of breast cancer stem cells

Lei¹,

Hu²,

Feng³

et al. 2020

Preprint

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Background: CD44 is an important surface marker of breast cancer stem cells (BCSCs), but it is unclear whether it is involved in the stemness of BCSCs. This has limited the development of new therapeutic strategies for breast cancer. Previous studies have shown that many CD44 variants generated through alternative splicing are involved in the development of breast cancer, but their exact role in BCSCs remains unclear. Therefore, we analyzed the CD44 transcript variants in BCSCs derived from the MDA-MB-435 cell line, and aimed to investigate whether CD44s knockdown could affect the biological characteristics of BCSCs.Methods: CD44+/CD24- cells were isolated among the MDA-MB-435 cells by flow cytometry, and the CD44 transcript variants were detected by RT-PCR in CD44+/CD24- cells. Due to the high expression of CD44 standard splice isoform (CD44s) in CD44+/CD24- cells, CD44s knockdown was generated using small hairpin RNA (shRNA). The effects of CD44s knockdown on the biological characteristics of BCSCs was detected using cell proliferation assay, colony formation assay, cell cycle and apoptosis assay, tumor sphere formation assay, would-healing assay, and Matrigel invasion assay. Tumorigenesis of the CD44+/CD24- cells with CD44s knockdown was investigated in vivo with NOD/SCID mice. The expression of cancer stem cell stemness-related genes, such as Bcl-2, CCNE2, EGFR, MMP7, Muc1, and Myc was also detected by qPCR.Results: Our results revealed that the mRNA expression of CD44 transcript variants was heterogeneous, and CD44s is highly expressed in BCSCs. CD44s depletion inhibited the proliferation, made cell cycle stay in G0/G1 phase, promoted the apoptosis and necrosis of BCSCs, inhibited the ability of self-renewal and invasion along with the expression of cancer stem cell-related genes in BCSCs. Moreover, CD44s knockdown inhibited the tumorigenesis ability in vivo.Conclusion: Our findings revealed that CD44s is the predominant isoform expressed in BCSCs, and is an important molecule for maintaining the properties of BCSCs. Targeting CD44s in BCSCs may be a potential new direction for breast cancer treatment.

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CD44s is a crucial ATG7 downstream regulator for stem-like property, invasion, and lung metastasis of human bladder cancer (BC) cells

Cited by 41 publications

References 70 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

A Feedback Loop Formed by ATG7/Autophagy, FOXO3a/miR-145 and PD-L1 Regulates Stem-like Properties and Invasion in Human Bladder Cancer

Effect of CD44 knockdown on the biological characteristics of breast cancer stem cells

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