Invasive oral cancer stem cells display resistance to ionising radiation

Gemenetzidis, Emilios; Gammon, Luke; Biddle, Adrian; Emich, Helena; Mackenzie, Ian C.

doi:10.18632/oncotarget.6268

Cited by 34 publications

(30 citation statements)

References 42 publications

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“…In addition, in this study, we observed a significant decrease in the mRNA expression of SNAI2 ( SLUG ), a transcription factor that participates in the EMT process. The EMT-CSC fraction in OSCC exhibits significant resistance to radiation and various chemotherapeutic agents ( 6 , 10 ). As it is responsible for tumour invasion and metastasis, therapies that can reduce or eradicate this cell fraction are greatly needed ( 77 ).…”

Section: Discussionmentioning

confidence: 99%

“…These cells are characterised by the ability to self-renew indefinitely, in addition to giving rise to transient and differentiated cells which comprise the bulk of the tumour ( 5 - 7 ). CSCs are therefore associated with recurrence and therapeutic resistance, and participate in OSCC metastasis due to their capability to undergo epithelial to mesenchymal transition (EMT) ( 8 - 10 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

GLI3 knockdown decreases stemness, cell proliferation and invasion in oral squamous cell carcinoma

Rodrigues

Miguita²,

Andrade³

et al. 2018

Int J Oncol

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Oral squamous cell carcinoma (OSCC) is an extremely aggressive disease associated with a poor prognosis. Previous studies have established that cancer stem cells (CSCs) actively participate in OSCC development, progression and resistance to conventional treatments. Furthermore, CSCs frequently exhibit a deregulated expression of normal stem cell signalling pathways, thereby acquiring their distinctive abilities, of which self-renewal is an example. In this study, we examined the effects of GLI3 knockdown in OSCC, as well as the differentially expressed genes in CSC-like cells (CSCLCs) expressing high (CD44high) or low (CD44low) levels of CD44. The prognostic value of GLI3 in OSCC was also evaluated. The OSCC cell lines were sorted based on CD44 expression; gene expression was evaluated using a PCR array. Following this, we examined the effects of GLI3 knockdown on CD44 and ESA expression, colony and sphere formation capability, stem-related gene expression, proliferation and invasion. The overexpression of genes related to the Notch, transforming growth factor (TGF)β, FGF, Hedgehog, Wnt and pluripotency maintenance pathways was observed in the CD44high cells. GLI3 knockdown was associated with a significant decrease in different CSCLC fractions, spheres and colonies in addition to the downregulation of the CD44, Octamer-binding transcription factor 4 (OCT4; also known as POU5F1) and BMI1 genes. This downregulation was accompanied by an increase in the expression of the Involucrin (IVL) and S100A9 genes. Cellular proliferation and invasion were inhibited following GLI3 knockdown. In OSCC samples, a high GLI3 expression was associated with tumour size but not with prognosis. On the whole, the findings of this study demonstrate for the first time, at least to the best of our knowledge, that GLI3 contributes to OSCC stemness and malignant behaviour. These findings suggest the potential for the development of novel therapies, either in isolation or in combination with other drugs, based on CSCs in OSCC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

GLI3 knockdown decreases stemness, cell proliferation and invasion in oral squamous cell carcinoma

Rodrigues

Miguita²,

Andrade³

et al. 2018

Int J Oncol

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“…Wnt/β-catenin signaling enhances LIG4 expression, and upregulation of LIG4 plays a key role in radioresistance in tissue stem cells and colorectal cancer cells [ 202 ]. Oral cancer stem cells display resistance to IR, and this correlates with elevated levels of XLF [ 203 ]. Collectively, the data suggest that the expression level of the core NHEJ factors impacts therapy responsiveness, with decreased expression resulting in radiosensitivity due to the inability of the cells to properly deal with DSBs, and increased expression resulting in radioresistance.…”

Section: Core Nhej Factors In Carcinogenesis and Cancermentioning

confidence: 99%

The Role of the Core Non-Homologous End Joining Factors in Carcinogenesis and Cancer

Sishc

Davis

2017

Cancers

130

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DNA double-strand breaks (DSBs) are deleterious DNA lesions that if left unrepaired or are misrepaired, potentially result in chromosomal aberrations, known drivers of carcinogenesis. Pathways that direct the repair of DSBs are traditionally believed to be guardians of the genome as they protect cells from genomic instability. The prominent DSB repair pathway in human cells is the non-homologous end joining (NHEJ) pathway, which mediates template-independent re-ligation of the broken DNA molecule and is active in all phases of the cell cycle. Its role as a guardian of the genome is supported by the fact that defects in NHEJ lead to increased sensitivity to agents that induce DSBs and an increased frequency of chromosomal aberrations. Conversely, evidence from tumors and tumor cell lines has emerged that NHEJ also promotes chromosomal aberrations and genomic instability, particularly in cells that have a defect in one of the other DSB repair pathways. Collectively, the data present a conundrum: how can a single pathway both suppress and promote carcinogenesis? In this review, we will examine NHEJ’s role as both a guardian and a disruptor of the genome and explain how underlying genetic context not only dictates whether NHEJ promotes or suppresses carcinogenesis, but also how it alters the response of tumors to conventional therapeutics.

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“…DNA damage clearance is a significant factor of radioresistance in cancer cells [19, 20] and γ-H2AX has been employed as a sensor of double-strained DNA breaks (DSBs) after γ-irradiation treatment [21]. Therefore, we investigated the effects of SKP2 expression on DNA damages after irradiation in HeLa and C33A cells which SKP2 expression was stably silenced or over-expressed.…”

Section: Resultsmentioning

confidence: 99%

Increased expression of SKP2 is an independent predictor of locoregional recurrence in cervical cancer via promoting DNA-damage response after irradiation

Yang

Chen

et al. 2016

Oncotarget

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Although radiation therapy was known to be effective to cervical cancer, loco-regional recurrences are frequently found in patients. We aimed to identify a molecular marker predicting the response of cervical cancer to radiotherapy. We included the patients (n = 149) with cervical cancer who had undergone radiotherapy from 2004 to 2006. Tumor samples were collected to examine the association between the expression of S-phase kinase-associated protein 2 (SKP2) and prognosis in cervical cancer. We found higher expression of SKP2 associated with recurrence (HRs: 2.52, p < 0.001), death (HRs: 2.01, p < 0.001) and higher locoregional recurrence rate (HRs: 3.76, p < 0.001). Cervical cancer cell lines with higher expression of SKP2 showed higher colony formation, cell survival rate and fewer DNA damages after irradiation. SKP2-C25, an inhibitor for SKP2 activity, dose-dependently decreased cell viability after irradiation and knockdown of SKP2 impaired DNA-damage response and sensitized the cervical cancer cells to irradiation. Our data showed the SKP2 represents a promising tool to identify patients with cervical cancer who have a higher risk of locoregional recurrence after radiotherapy. Targeting SKP2 may serve as a potential radiosensitizer for developing effective therapeutic strategies against cervical cancer.

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Invasive oral cancer stem cells display resistance to ionising radiation

Cited by 34 publications

References 42 publications

GLI3 knockdown decreases stemness, cell proliferation and invasion in oral squamous cell carcinoma

GLI3 knockdown decreases stemness, cell proliferation and invasion in oral squamous cell carcinoma

The Role of the Core Non-Homologous End Joining Factors in Carcinogenesis and Cancer

Increased expression of SKP2 is an independent predictor of locoregional recurrence in cervical cancer via promoting DNA-damage response after irradiation

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