The Molecular Basis and Therapeutic Aspects of Cisplatin Resistance in Oral Squamous Cell Carcinoma

Cheng, Yali; Li, Shaoming; Gao, Ling; Zhi, Kangkang; Ren, Wenhao

doi:10.3389/fonc.2021.761379

Cited by 63 publications

(39 citation statements)

References 180 publications

(146 reference statements)

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“…Moreover, it has shown a tumor growth delay when exposed to current standard chemotherapeutic regimens (20). However, chemotherapeutic agent selectivity kills proliferating cells over quiescent cells (21), triggering cancer stem cell enrichment (quiescent cells) and favoring resistance to chemotherapy (22). An example of that is the quiescent area increase in the treated spheroids in our results.…”

Section: Discussionmentioning

confidence: 53%

Automatic tool for analysis of morphometric changes in the tumor spheroids regions treated with cisplatin

Fonseca-Benítez

Casallas

Guarnizo-Mendez

et al. 2022

Preprint

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Spheroids provides an in vitro cell culture model that mimics cancer cell growth in the in vivo solid tumor microenvironment. This cell culture model has revolutionized drug response studies. The architecture of the spheroid allows the cells to form different layers depending on oxygen, nutrients, and pH gradients. These layers, called proliferative, quiescent, and necrotic zones, are relevant in the treatment response evaluation because the cells present there have different behavior, which provides a better approach to evaluate treatments that can be correlated to in vivo response. Consequently, a key aspect for evaluation in this culture type is to analyze its morphology features; this is added to the main problem in extracting all parameters necessary for analysis. To overcome this difficulty, in this work, we proposed a MATLAB script for analyzing layers or zones of CAL27 spheroids with automatic computation of different morphological parameters. We correlated with in vitro experiments to improve the development and evaluation of antitumor drugs. This analysis utilizes inverted microscopy imaging of squamous oral carcinoma cells growing in spheroids treated or untreated with cisplatin. We developed and tested a software tool that detects each zone of the spheroid from threshold values and the changes in treatment response. The morphological parameters sphericity and solidity changes were observed in spheroids treated and untreated with cisplatin 20µM in the different zones. Besides, we observed that the quiescent zone was increased after treatment.

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Section: Discussionmentioning

confidence: 53%

Automatic tool for analysis of morphometric changes in the tumor spheroids regions treated with cisplatin

Fonseca-Benítez

Casallas

Guarnizo-Mendez

et al. 2022

Preprint

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“…Since our findings in Fig. 5 indicated that depletion of KRT17 by miR485-5p elevated OSCC cellular sensitivity toward the frequently used first-line chemotherapeutics, cisplatin and carboplatin [ 54 , 55 ]. To further confirm those observations, we inhibited directly KRT17 by its siRNA in C9IV3 and HSC3 cells and tested their sensitivity toward cisplatin or carboplatin.…”

Section: Resultsmentioning

confidence: 99%

MicroRNA-485-5p targets keratin 17 to regulate oral cancer stemness and chemoresistance via the integrin/FAK/Src/ERK/β-catenin pathway

et al. 2022

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Background The development of drug resistance in oral squamous cell carcinoma (OSCC) that frequently leads to recurrence and metastasis after initial treatment remains an unresolved challenge. Presence of cancer stem cells (CSCs) has been increasingly reported to be a critical contributing factor in drug resistance, tumor recurrence and metastasis. Thus, unveiling of mechanisms regulating CSCs and potential targets for developing their inhibitors will be instrumental for improving OSCC therapy. Methods siRNA, shRNA and miRNA that specifically target keratin 17 (KRT17) were used for modulation of gene expression and functional analyses. Sphere-formation and invasion/migration assays were utilized to assess cancer cell stemness and epithelial mesenchymal transition (EMT) properties, respectively. Duolink proximity ligation assay (PLA) was used to examine molecular proximity between KRT17 and plectin, which is a large protein that binds cytoskeleton components. Cell proliferation assay was employed to evaluate growth rates and viability of oral cancer cells treated with cisplatin, carboplatin or dasatinib. Xenograft mouse tumor model was used to evaluate the effect of KRT17- knockdown in OSCC cells on tumor growth and drug sensitization. Results Significantly elevated expression of KRT17 in highly invasive OSCC cell lines and advanced tumor specimens were observed and high KRT17 expression was correlated with poor overall survival. KRT17 gene silencing in OSCC cells attenuated their stemness properties including markedly reduced sphere forming ability and expression of stemness and EMT markers. We identified a novel signaling cascade orchestrated by KRT17 where its association with plectin resulted in activation of integrin β4/α6, increased phosphorylation of FAK, Src and ERK, as well as stabilization and nuclear translocation of β-catenin. The activation of this signaling cascade was correlated with enhanced OSCC cancer stemness and elevated expression of CD44 and epidermal growth factor receptor (EGFR). We identified and demonstrated KRT17 to be a direct target of miRNA-485-5p. Ectopic expression of miRNA-485-5p inhibited OSCC sphere formation and caused sensitization of cancer cells towards cisplatin and carboplatin, which could be significantly rescued by KRT17 overexpression. Dasatinib treatment that inhibited KRT17-mediated Src activation also resulted in OSCC drug sensitization. In OSCC xenograft mouse model, KRT17 knockdown significantly inhibited tumor growth, and combinatorial treatment with cisplatin elicited a greater tumor inhibitory effect. Consistently, markedly reduced levels of integrin β4, active β-catenin, CD44 and EGFR were observed in the tumors induced by KRT17 knockdown OSCC cells. Conclusions A novel miRNA-485-5p/KRT17/integrin/FAK/Src/ERK/β-catenin signaling pathway is unveiled to modulate OSCC cancer stemness and drug resistance to the common first-line chemotherapeutics. This provides a potential new therapeutic strategy to inhibit OSCC stem cells and counter chemoresistance.

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“…Cisplatin-based chemotherapy is the first-line chemotherapy agent for OSCC [12]. Cisplatin covalently binds to the N7 position of the purine base of DNA, forming adducts such as intra-strand cross links, which trigger cytotoxicity [45].…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, blocking DNA repair pathway is an important approach for tumor treatment. For instance, cisplatin, the first-line chemotherapeutic drug for OSCC, induces DNA damage through the formation of cisplatin-DNA adducts, leading to cell cycle arrest and apoptosis [ 12 ]. Nucleotide excision repair is a key pathway to resist damage caused by cisplatin [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

HMG20A was identified as a key enhancer driver associated with DNA damage repair in oral squamous cell carcinomas

Zhang

Wenjing

et al. 2022

BMC Oral Health

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Background Oral squamous cell carcinoma (OSCC) is the main type of oral cancer. Disturbing DNA repair is an invaluable way to improve the effectiveness of tumor treatment. Here, we aimed to explore the key enhancer drivers associated with DNA damage repair in OSCC cells. Methods Gene Set Enrichment Analysis (GSEA), Gene Set Variation Analysis (GSVA) and Kaplan-Meier analysis were applied to explore the relationship among DNA repair-related genes expression and clinical phenotypes based on The Cancer Genome Atlas (TCGA) database. HOMER software and Integrative Genomics Viewer were applied to identify and visualize enhancers using GSE120634. Toolkit for Cistrome Data Browser was applied to predict transcription factors. Human Protein Atlas Database was used to analyze the protein levels of transcription factors in OSCC and control tissues. Seventy-two OSCC patients were included in this study. qRT-PCR was used to detect transcription factor expression in OSCC and adjacent control tissues collected in this study. qRT-PCR and ChIP-qPCR were used to verify the binding of transcription factors to enhancers, and regulation of target genes transcription. Transcription factor knockdown and control cells were treated with cisplatin. CCK8 was used to detect cell viability and proliferation. Western blotting was implemented to detect the levels of DNA repair-related proteins. Transwell assay was used to detect cell invasion. Results DNA repair was positively associated with the OSCC metastatic phenotype. Patients in the cluster with high expression of DNA repair-related genes had a worse prognosis and a higher proportion of advanced stage, low-differentiation, alcohol consumption and smoking compared to the cluster with low DNA repair-related gene expression. Seventeen metastasis-specific enhancer-controlled upregulated DNA repair-related genes, with the top two upregulated genes being ADRM1 26 S proteasome ubiquitin receptor (ADRM1) and solute carrier family 12 member 7 (SLC12A7) were screened. High mobility group 20 A (HMG20A) was the key prognostic enhancer driver regulating metastasis-specific DNA repair-related genes, with higher expression in OSCC tissues than normal control tissues, and higher expression in metastatic OSCC tissues than non-metastatic OSCC tissues. HMG20A bound to the metastasis-specific enhancers of ADRM1 and SLC12A7, thereby promoting ADRM1 and SLC12A7 expression. Knockdown of HMG20A enhanced cisplatin sensitivity of cells, and inhibited OSCC cells from repairing DNA damage caused by cisplatin, as well as proliferation and invasion of OSCC cells. Conclusion HMG20A was identified as the key prognostic enhancer driver regulating DNA repair in OSCC cells, providing a new therapeutic target for OSCC.

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The Molecular Basis and Therapeutic Aspects of Cisplatin Resistance in Oral Squamous Cell Carcinoma

Cited by 63 publications

References 180 publications

Automatic tool for analysis of morphometric changes in the tumor spheroids regions treated with cisplatin

Automatic tool for analysis of morphometric changes in the tumor spheroids regions treated with cisplatin

MicroRNA-485-5p targets keratin 17 to regulate oral cancer stemness and chemoresistance via the integrin/FAK/Src/ERK/β-catenin pathway

HMG20A was identified as a key enhancer driver associated with DNA damage repair in oral squamous cell carcinomas

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