<scp>TGF</scp>‐β1‐induced <scp>CK</scp>17 enhances cancer stem cell‐like properties rather than <scp>EMT</scp> in promoting cervical cancer metastasis via the <scp>ERK</scp>1/2‐<scp>MZF</scp>1 signaling pathway

Wu, Lan-Fang; Han, Lu; Zhou, Chenfei; Wei, W.; Chen, Xiaojing; Yi, Hongyan; Wu, Xinglong; Bai, Xiaojing; Guo, Suiqun; Yu, Yang; Li, Liang; Wang, Wei

doi:10.1111/febs.14162

Cited by 49 publications

(47 citation statements)

References 49 publications

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“…105 Findings in a cervical cancer study showed that TGF-β1 promoted EMT in cancer cells and helped them to obtain a CSC phenotype. 80 Similarly, in hepatocellular carcinoma, TGF-β1 could achieve the same effect as in cervical cancer by downregulating TP53INP1 through miR-155. 78 These studies suggest that the radiation-induced TGF-β signalling pathway plays an important role in EMT and obtaining a CSC phenotype, thereby promoting tumour metastasis.…”

Section: Csc-associated Epithelial-mesenchymal Transitionmentioning

confidence: 98%

“…In addition, it has been confirmed by evidence that CSCs have mesenchymal phenotypes, suggesting their high capacity for migration and invasion. [78][79][80] IR can induce non-CSCs to have stronger migration activity, which is closely related to the acquisition of the CSC phenotype and radiation-induced epithelial-mesenchymal transformation (EMT), 58 which is associated with relapse and metastasis.…”

Section: Csc-associated Relapse and Metastasis In Oral Cancer Post-ramentioning

confidence: 99%

“…Therefore, it is widely believed that cancer cells that have undergone EMT have stronger migration activity than those that retain an epithelial phenotype. [94][95][96] There is increasing evidence that CSCs have mesenchymal cell phenotypes, [78][79][80] which can ultimately lead to tumour metastasis. It has been found in nasopharyngeal carcinoma that nasopharyngeal carcinoma cell lines surviving radiation treatment show decreased E-cadherin and increased vimentin, resulting in EMT occurrence with strong migration activity.…”

Section: Csc-associated Epithelial-mesenchymal Transitionmentioning

confidence: 99%

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Radiotherapy targeting cancer stem cells “awakens” them to induce tumour relapse and metastasis in oral cancer

et al. 2020

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Radiotherapy is one of the most common treatments for oral cancer. However, in the clinic, recurrence and metastasis of oral cancer occur after radiotherapy, and the underlying mechanism remains unclear. Cancer stem cells (CSCs), considered the "seeds" of cancer, have been confirmed to be in a quiescent state in most established tumours, with their innate radioresistance helping them survive more easily when exposed to radiation than differentiated cancer cells. There is increasing evidence that CSCs play an important role in recurrence and metastasis post-radiotherapy in many cancers. However, little is known about how oral CSCs cause tumour recurrence and metastasis post-radiotherapy. In this review article, we will first summarise methods for the identification of oral CSCs and then focus on the characteristics of a CSC subpopulation induced by radiation, hereafter referred to as "awakened" CSCs, to highlight their response to radiotherapy and potential role in tumour recurrence and metastasis post-radiotherapy as well as potential therapeutics targeting CSCs. In addition, we explore potential therapeutic strategies targeting these "awakened" CSCs to solve the serious clinical challenges of recurrence and metastasis in oral cancer after radiotherapy.

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Section: Csc-associated Epithelial-mesenchymal Transitionmentioning

confidence: 98%

Section: Csc-associated Relapse and Metastasis In Oral Cancer Post-ramentioning

confidence: 99%

Section: Csc-associated Epithelial-mesenchymal Transitionmentioning

confidence: 99%

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Radiotherapy targeting cancer stem cells “awakens” them to induce tumour relapse and metastasis in oral cancer

et al. 2020

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“…The association between 1,25 (OH) 2 D 3 and TGF-β/Smad signaling pathway 28,29 led us to consider whether TGF-β/Smad signaling pathway induces the IRX4-induced cancer stem cell-like properties. Studies have shown that TGF-β1 signaling promotes cancer cell stemness, leading to tumor metastasis 30,31 . Whether TGF-β1 increased cancer cell stemness by regulating IRX4 and how to regulate TGF-β1 signaling mediated cancer stem-like properties is unclear.…”

Section: Discussionmentioning

confidence: 99%

1,25-dihydroxyvitamin D3 signaling-induced decreases in IRX4 inhibits NANOG-mediated cancer stem-like properties and gefitinib resistance in NSCLC cells

et al. 2020

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Recent studies have demonstrated that acquisition of cancer stem-like properties plays an essential role in promoting epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) resistance in non-small cell lung cancer (NSCLC); however, how to regulate cancer stem-like properties and EGFR-TKI resistance is largely unclear. In this study, we discovered that increased iroquois-class homeodomain protein 4 (IRX4) was related to gefitinib resistance in NSCLC cells. Knockdown of IRX4 inhibited cell proliferation, sphere formation, and the expression of CD133, ALDH1A1, NANOG, Sox2 and Notch1, and the transcriptional activity of NANOG promoter. IRX4 overexpression increased the protein level of NANOG and CD133 in PC-9 cells. Combination of knocking-down IRX4 with gefitinib increased cell apoptosis and decreased cell viability and the expression of p-EGFR and NANOG in PC-9/GR cells. IRX4 knockdown in a PC-9/GR xenograft tumor model inhibited tumor progression and the expression of NANOG and CD133 more effectively than single treatment alone. Knockdown of NANOG inhibited the expression of CD133 and restored gefitinib cytotoxicity, and NANOG overexpression-induced cancer stem-like properties and gefitinib resistance could be obviously reversed by knocking-down IRX4. Further, we found that 1,25-dihydroxyvitamin D3 (1,25(OH) 2 D 3) reduced obviously the expression of IRX4 and NANOG by inhibiting the activation of TGF-β1/Smad3 signaling pathway; moreover, combination of 1,25(OH) 2 D 3 and gefitinib decreased cell viability and proliferation or tumor progression and the expression of IRX4 and NANOG compared with single treatment alone both in PC-9/GR cells and in a PC-9/GR xenograft tumor model. These results reveal that inhibition of IRX4-mediated cancer stem-like properties by regulating 1,25(OH) 2 D 3 signaling may increase gefitinib cytotoxicity. Combination therapy of gefitinib and 1,25 (OH) 2 D 3 by targeting IRX4 and NANOG, could provide a promising strategy to improve gefitinib cytotoxicity.

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“…Keratinocyte differentiation, skin development and epidermis development gene sets enriched in the high PPS20 group include many genes belonging to the keratin family, among which KRT16 has been used as a basal cell marker [28,29]; KRT17 has been shown to induce cancer stem cell-like properties in cervical cancer [30] and tumor growth, motility and invasion in gastric cancer [31], which is also associated with poor prognosis in breast cancer [32]. Formation of primary germ layer and endoderm gene sets were also enriched in tumors with high PPS20.…”

Section: Molecular Characteristics Of Pps20-identified Pdac Sub-groupsmentioning

confidence: 99%

A novel 20-gene prognostic score in pancreatic adenocarcinoma

et al. 2020

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Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Known risk factors for this disease are currently insufficient in predicting mortality. In order to better prognosticate patients with PDAC, we identified 20 genes by utilizing publically available high-throughput transcriptomic data from GEO, TCGA and ICGC which are associated with overall survival and event-free survival. A score generated based on the expression matrix of these genes was validated in two independent cohorts. We find that this "Pancreatic cancer prognostic score 20-PPS20" is independent of the confounding factors in multivariate analyses, is dramatically elevated in metastatic tissue compared to primary tumor, and is higher in primary tumors compared to normal pancreatic tissue. Transcriptomic analyses show that tumors with low PPS20 have overall more immune cell infiltration and a higher CD8 T cell/Treg ratio when compared to those with high PPS20. Analyses of proteomic data from TCGA PAAD indicated higher levels of Cyclin B1, RAD51, EGFR and a lower E-cadherin/Fibronectin ratio in tumors with high PPS20. The PPS20 score defines not only prognostic and biological subgroups but can predict response to targeted therapy as well. Overall, PPS20 is a stronger and more robust transcriptomic signature when compared to similar, previously published gene lists.

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TGF‐β1‐induced CK17 enhances cancer stem cell‐like properties rather than EMT in promoting cervical cancer metastasis via the ERK1/2‐MZF1 signaling pathway

Cited by 49 publications

References 49 publications

Radiotherapy targeting cancer stem cells “awakens” them to induce tumour relapse and metastasis in oral cancer

Radiotherapy targeting cancer stem cells “awakens” them to induce tumour relapse and metastasis in oral cancer

1,25-dihydroxyvitamin D3 signaling-induced decreases in IRX4 inhibits NANOG-mediated cancer stem-like properties and gefitinib resistance in NSCLC cells

A novel 20-gene prognostic score in pancreatic adenocarcinoma

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