CD44 promotes hepatocellular carcinoma progression via upregulation of YAP

Zhang, Jun; He, Xilin; Wan, Yajie; Zhang, Honghong; Tang, Tao; Zhang, Meng; Yu, Shiyi; Zhao, Weiyong; Chen, Liming

doi:10.1186/s40164-021-00247-w

Cited by 18 publications

(20 citation statements)

References 12 publications

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“…Similar, but not identical, regulatory relationships have been observed in other cancer types. For example, SFN treatment reduces CD44v6 level in prostate cancer, 46 SFN reduces CD44 and ALDH1 in oral squamous cell carcinoma, 47 CD44 knockdown reduces YAP1 signaling and YAP1 target gene expression in lung cancer, 29 CD44/YAP1 cooperation has been described in hepatocellular carcinoma 30 and CD44 modulates ERK1/2, Akt and YAP1 signaling 31 . Our present studies link SFN, CD44v6 and YAP1/TEAD in a single pathway.…”

Section: Discussionsupporting

confidence: 60%

“…In CSCC, YAP1/TEAD target genes include CYR61, CCND1, CTGF, and the procancer collagen genes, COL1A2 and COL3A1 25 . However, it is increasingly apparent that multiple mechanisms control YAP1/TEAD function 26–28 and recent studies show that CD44 can regulate YAP1 signaling and YAP1 target gene expression in several cancer types 29–31 …”

Section: Introductionmentioning

confidence: 99%

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Sulforaphane inhibits CD44v6/YAP1/TEAD signaling to suppress the cancer phenotype

Chen

Adhikary

et al. 2022

Molecular Carcinogenesis

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Sulforaphane (SFN) is a promising cancer prevention and treatment agent that strongly suppresses the cutaneous squamous cell carcinoma (CSCC) cell cancer phenotype. We previously showed that yes-associated protein 1 (YAP1)/TEAD signaling is a key procancer stimulator of the aggressive CSCC cell cancer phenotype. However, SFN-responsive upstream regulators of YAP1/TEAD signaling are not well characterized and so there is a pressing need to identify these factors.We show that CD44v6 knockdown reduces YAP1/TEAD-dependent transcription and target gene expression, and that this is associated with reduced spheroid formation, invasion and migration. CD44v6 knockout cell lines also display reduced YAP1/TEAD activity and target gene expression and attenuated spheroid formation, invasion, migration and tumor formation. An important finding is that SFN treatment suppresses CD44v6 level leading to a reduction in YAP1/TEAD signaling and marker gene expression. Sox2 level and epithelial-mesenchymal transition (EMT) are also reduced. Forced expression of constitutive active YAP1 in CD44v6 knockdown cells partially restores the aggressive cancer phenotype. These important findings suggest that CD44v6 drives YAP1/TEAD signaling to enhance the CSCC cell cancer phenotype and that SFN treatment reduces CD44v6 level/function which, in turn, reduces YAP1/TEAD signaling leading to reduced stemness, EMT and tumor growth.

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Section: Discussionsupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Sulforaphane inhibits CD44v6/YAP1/TEAD signaling to suppress the cancer phenotype

Chen

Adhikary

et al. 2022

Molecular Carcinogenesis

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“…The Hippo signaling pathway acts a significant role in mediating cell division, proliferation, differentiation, and apoptosis. YES-associated protein (YAP) is an effector of this pathway, which could initiate the gene transcription and translation of the Hippo pathway [ 92 , 93 ]. YTHDF2 was found to reduce the levels of the classical Hippo signal transduction factors, including YAP, LATS1 and Mob1 [ 56 ].…”

Section: Molecular Mechanisms Of Ythdf2 In Tumorigenesismentioning

confidence: 99%

m6A binding protein YTHDF2 in cancer

2022

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YT521-B homology domain family member 2 (YTHDF2) is an N6-methyladenosine (m6A)-binding protein that was originally found to regulate the stability of mRNA. Growing evidence has shown that YTHDF2 can participate in multifarious bioprocesses, including embryonic development, immune response, and tumor progression. Furthermore, YTHDF2 is closely associated with the proliferation, apoptosis, invasion, and migration of tumor cells, suggesting its significant role in cancers. YTHDF2 primarily relies on m6A modification to modulate signaling pathways in cancer cells. However, the expression and function of YTHDF2 in human malignancies remain controversial. Meanwhile, the underlying molecular mechanisms of YTHDF2 have not been elucidated. In this review, we principally summarized the biological functions and molecular mechanisms of YTHDF2 in tumors and discussed its prognostic and therapeutic values.

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“…It has been reported that CD44 promotes stemness and metastasis in various cancers, including breast cancer [ 15 , 19 , 21 , 49 , 50 , 51 , 52 ]. It is also well-documented that CD44 promotes cancer cell migration and invasion via mesenchymal markers [ 49 , 53 , 54 , 55 ].…”

Section: Discussionmentioning

confidence: 99%

CD44 Promotes Breast Cancer Metastasis through AKT-Mediated Downregulation of Nuclear FOXA2

et al. 2022

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The primary cause of breast cancer mortality is the metastatic invasion of cancerous stem cells (CSC). Cluster of differentiation 44 (CD44) is a well-known CSC marker in various cancers, as well as a key role player in metastasis and relapse of breast cancer. CD44 is a cell-membrane embedded protein, and it interacts with different proteins to regulate cancer cell behavior. Transcription factor forkhead box protein A2 (FOXA2) acts as an important regulator in multiple cancers, including breast cancer. However, the biological significance of CD44-FOXA2 association in breast cancer metastasis remains unclear. Herein, we observed that CD44 expression was higher in metastatic lymph nodes compared to primary tumors using a flow cytometric analysis. CD44 overexpression in breast cancer cell lines significantly promoted cell migration and invasion abilities, whereas the opposite effects occurred upon the knockdown of CD44. The stem cell array analysis revealed that FOXA2 expression was upregulated in CD44 knockdown cells. However, the knockdown of FOXA2 in CD44 knockdown cells reversed the effects on cell migration and invasion. Furthermore, we found that CD44 mediated FOXA2 localization in breast cancer cells through the AKT pathway. Moreover, the immunofluorescence assay demonstrated that AKT inhibitor wortmannin and AKT activator SC79 treatment in breast cancer cells impacted FOXA2 localization. Collectively, this study highlights that CD44 promotes breast cancer metastasis by downregulating nuclear FOXA2.

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CD44 promotes hepatocellular carcinoma progression via upregulation of YAP

Cited by 18 publications

References 12 publications

Sulforaphane inhibits CD44v6/YAP1/TEAD signaling to suppress the cancer phenotype

Sulforaphane inhibits CD44v6/YAP1/TEAD signaling to suppress the cancer phenotype

m6A binding protein YTHDF2 in cancer

CD44 Promotes Breast Cancer Metastasis through AKT-Mediated Downregulation of Nuclear FOXA2

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