The role of epithelial-mesenchymal transition in regulating radioresistance

Zhou, Suna; Zhang, Mingxin; Zhou, Chao; Wang, Wei; Yang, Haihua; Ye, Wenguang

doi:10.1016/j.critrevonc.2020.102961

Cited by 49 publications

(39 citation statements)

References 110 publications

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“…miR-221-3p and miR-222-3p reduce radiosensitivity in thyroid cancer cells. It was previously reported that EMT was associated with decreased cancer sensitivity to radiation therapy (22)(23)(24)(25). Therefore, a colony formation assay was used to determine the role of miR-221-3p and miR-222-3p in radiosensitivity.…”

Section: Mir-221-3p and Mir-222-3p Regulate The Expression Levels Of P-stat3 Emt-related Markers And Nis In Thyroid Cancer Cellsmentioning

confidence: 99%

miR‑221‑3p and miR‑222‑3p regulate the SOCS3/STAT3 signaling pathway to downregulate the expression of NIS and reduce radiosensitivity in thyroid cancer

Zhong

et al. 2021

Exp Ther Med

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The expression levels of microRNA (miR)-221-3p and miR-222-3p in thyroid cancer have been found to be upregulated compared with those in normal tissues. The present study aimed to determine the effects and potential underlying mechanisms of miR-221-3p and miR-222-3p on the regulation of radioactive iodine ( 131 I) uptake and radiosensitivity of thyroid cancer cells. The potential regulatory target genes of miR-221-3p and miR-222-3p were predicted by bioinformatics analysis, and reverse transcription-quantitative polymerase chain reaction was used to verify miR-221-3p, miR-222-3p and target gene expression levels in thyroid cancer tissues and cell lines. Overexpression of miR-221-3p or miR-222-3p in cell models was performed using lentivirus infection. Knockdown of miR-221-3p and miR-222-3p in cells was achieved using oligonucleotide inhibitor transfection.Western blotting was used to analyze the expression levels of target proteins. In addition, the effects of miR-221-3p and miR-222-3p on the radiosensitivity of thyroid cancer cells were verified using a colony formation assay. The results of the present study revealed that the expression levels of miR-221-3p and miR-222-3p were significantly upregulated, while the expression levels of suppressor of cytokine signaling 3 (SOCS3) were downregulated in thyroid cancer tissues. Furthermore, miR-221-3p and miR-222-3p overexpression downregulated the expression levels of SOCS3, E-cadherin and solute carrier family 5 member 5 (NIS), and upregulated the expression levels of phosphorylated STAT3 and vimentin. Following the overexpression of miR-221-3p or miR-222-3p in the FTC133 and TPC1 cell lines, their radiosensitivity was suppressed. In conclusion, the findings of the present study suggested that miR-221-3p and miR-222-3p may downregulate the expression levels of NIS and promote radioresistance. The potential mechanism was hypothesized to be associated with the miR-221-3p and miR-222-3p targeting of the SOCS3 gene, which may subsequently activate the STAT3 signaling pathway.

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Section: Mir-221-3p and Mir-222-3p Regulate The Expression Levels Of P-stat3 Emt-related Markers And Nis In Thyroid Cancer Cellsmentioning

confidence: 99%

miR‑221‑3p and miR‑222‑3p regulate the SOCS3/STAT3 signaling pathway to downregulate the expression of NIS and reduce radiosensitivity in thyroid cancer

Zhong

et al. 2021

Exp Ther Med

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“…Well known that EMT-related signaling pathways contribute to tumor cell reprogramming into CSCs, metastatic tumor spread, and radioresistance [19,[44][45][46][47]. In our previous study [38], MFR-surviving p53null subline of NSCLC cells demonstrated a significant decrease in the kinetics of IR Induced Nuclear Foci (IRIF) number (pATM иγH2AX) com-pared to parental cells during 8 h after single 2 Gy IR exposure.…”

Section: Cd44high/cd166high (Csc-like) Population In Parental and Mfrmentioning

confidence: 92%

The CD44high Subpopulation of Multifraction Irradiation-Surviving NSCLC Cells Exhibits Partial EMT-Program Activation and DNA Damage Response Depending on Their p53 Status

Pustovalova

Alhaddad

Blokhina

et al. 2021

IJMS

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Ionizing radiation (IR) is used for patients diagnosed with unresectable non-small cell lung cancer (NSCLC). However, radiotherapy remains largely palliative due to the survival of specific cell subpopulations. In the present study, the sublines of NSCLC cells, A549IR (p53wt) and H1299IR (p53null) survived multifraction X-ray radiation exposure (MFR) at a total dose of 60 Gy were investigated three weeks after the MFR course. We compared radiosensitivity (colony formation), expression of epithelial-mesenchymal transition (EMT) markers, migration activity, autophagy, and HR-dependent DNA double-strand break (DSB) repair in the bulk and entire CD44high/CD166high CSC-like populations of both parental and MFR survived NSCLC cells. We demonstrated that the p53 status affected: the pattern of expression of N-cadherin, E-cadherin, Vimentin, witnessing the appearance of EMT-like phenotype of MFR-surviving sublines; 1D confined migratory behavior (wound healing); the capability of an irradiated cell to continue to divide and form a colony of NSCLC cells before and after MFR; influencing the CD44/CD166 expression level in MFR-surviving NSCLC cells after additional single irradiation. Our data further emphasize the impact of p53 status on the decay of γH2AX foci and the associated efficacy of the DSB repair in NSCLC cells survived after MFR. We revealed that Rad51 protein might play a principal role in MFR-surviving of p53 null NSCLC cells promoting DNA DSB repair by homologous recombination (HR) pathway. The proportion of Rad51 + cells elevated in CD44high/CD166high population in MFR-surviving p53wt and p53null sublines and their parental cells. The p53wt ensures DNA-PK-mediated DSB repair for both parental and MFR-surviving cells irrespectively of a subsequent additional single irradiation. Whereas in the absence of p53, a dose-dependent increase of DNA-PK-mediated non-homologous end joining (NHEJ) occurred as an early post-irradiation response is more intensive in the CSC-like population MFR-surviving H1299IR, compared to their parental H1299 cells. Our study strictly observed a significantly higher content of LC3 + cells in the CD44high/CD166high populations of p53wt MFR-surviving cells, which enriched the CSC-like cells in contrast to their p53null counterparts. The additional 2 Gy and 5 Gy X-ray exposure leads to the dose-dependent increase in the proportion of LC3 + cells in CD44high/CD166high population of both parental p53wt and p53null, but not MFR-surviving NSCLC sublines. Our data indicated that autophagy is not necessarily associated with CSC-like cells’ radiosensitivity, emphasizing that careful assessment of other milestone processes (such as senescence and autophagy-p53-Zeb1 axis) of primary radiation responses may provide new potential targets modulated for therapeutic benefit through radiosensitizing cancer cells while rescuing normal tissue. Our findings also shed light on the intricate crosstalk between autophagy and the p53-related EMT, by which MFR-surviving cells might obtain an invasive phenotype and metastatic potential.

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“…Cancer stem cells (CSCs) and epithelial to mesenchymal transition (EMT) play a critical role in resistance to treatment [ 67 , 68 , 69 ]. CSCs are characterised by their capacity to self-renew and to generate multiple cell types along with cell division and tumour expansion.…”

Section: Pushing Forward Loco-regional Control: Modern Rtmentioning

confidence: 99%

“…During EMT, cancer cells undergo morphological changes and reorganise the cytoskeleton, resulting in increased motility and invasion abilities [ 74 ]. Besides its role in metastasis, a correlation between an EMT phenotype and chemo- or radioresistance has been established in cancer cells and notably in PDAC [ 69 , 75 , 76 , 77 ]. Several pathways, such as TGFβ, Wnt, Notch, EGFR, ERK or PI3K/AKT, are activated by RT or CT and promote the EMT phenotype.…”

Section: Pushing Forward Loco-regional Control: Modern Rtmentioning

confidence: 99%

“…Several pathways, such as TGFβ, Wnt, Notch, EGFR, ERK or PI3K/AKT, are activated by RT or CT and promote the EMT phenotype. Subsequently, EMT can trigger transcription factors implicated in resistance (Snail, ZEB or Twist superfamily) [ 68 , 69 , 72 , 77 , 78 , 79 ]. Some of these pathways or regulators overlap with the ones activated by CSCs in PDAC such as TGFβ [ 80 ], Slug (Snail2) [ 81 , 82 ] or Notch1 [ 68 ].…”

Section: Pushing Forward Loco-regional Control: Modern Rtmentioning

confidence: 99%

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Could Protons and Carbon Ions Be the Silver Bullets Against Pancreatic Cancer?

Huart

Chen

Calvé

et al. 2020

IJMS

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Pancreatic cancer is a very aggressive cancer type associated with one of the poorest prognostics. Despite several clinical trials to combine different types of therapies, none of them resulted in significant improvements for patient survival. Pancreatic cancers demonstrate a very broad panel of resistance mechanisms due to their biological properties but also their ability to remodel the tumour microenvironment. Radiotherapy is one of the most widely used treatments against cancer but, up to now, its impact remains limited in the context of pancreatic cancer. The modern era of radiotherapy proposes new approaches with increasing conformation but also more efficient effects on tumours in the case of charged particles. In this review, we highlight the interest in using charged particles in the context of pancreatic cancer therapy and the impact of this alternative to counteract resistance mechanisms.

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The role of epithelial-mesenchymal transition in regulating radioresistance

Cited by 49 publications

References 110 publications

miR‑221‑3p and miR‑222‑3p regulate the SOCS3/STAT3 signaling pathway to downregulate the expression of NIS and reduce radiosensitivity in thyroid cancer

miR‑221‑3p and miR‑222‑3p regulate the SOCS3/STAT3 signaling pathway to downregulate the expression of NIS and reduce radiosensitivity in thyroid cancer

The CD44high Subpopulation of Multifraction Irradiation-Surviving NSCLC Cells Exhibits Partial EMT-Program Activation and DNA Damage Response Depending on Their p53 Status

Could Protons and Carbon Ions Be the Silver Bullets Against Pancreatic Cancer?

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