LncRNAs as Regulators of Autophagy and Drug Resistance in Colorectal Cancer

Bermúdez, Mercedes; Aguilar‐Medina, Maribel; Lizárraga-Verdugo, Erik; Avendaño-Félix, Mariana; Silva-Benítez, Erika de Lourdes; López-Camarillo, César; Ramos‐Payán, Rosalío

doi:10.3389/fonc.2019.01008

Cited by 92 publications

(82 citation statements)

References 199 publications

(190 reference statements)

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“…The loss of these miRNAs was associated with increased activity of the DNA damage and repair machinery and subsequent resistance to chemotherapy. Besides miRNAs, there is evidence that lncRNAs can also play a significant role in cancer progression, metastasis (Chen et al, 2018), and chemoresistance (Bermudez et al, 2019). For instance, overexpression of lncRNA SBF2-AS1 led to the promotion of temozolomide chemoresistance in glioblastoma cells and tissues via a ZEB1-dependent pathway.…”

Section: Interplay Between Micrornas Zeb1 and Dna Damage Responsementioning

confidence: 99%

ZEB1: A Critical Regulator of Cell Plasticity, DNA Damage Response, and Therapy Resistance

Drápela

Bouchal

Jolly

et al. 2020

Front. Mol. Biosci.

124

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The predominant way in which conventional chemotherapy kills rapidly proliferating cancer cells is the induction of DNA damage. However, chemoresistance remains the main obstacle to therapy effectivity. An increasing number of studies suggest that epithelial-to-mesenchymal transition (EMT) represents a critical process affecting the sensitivity of cancer cells to chemotherapy. Zinc finger E-box binding homeobox 1 (ZEB1) is a prime element of a network of transcription factors controlling EMT and has been identified as an important molecule in the regulation of DNA damage, cancer cell differentiation, and metastasis. Recent studies have considered upregulation of ZEB1 as a potential modulator of chemoresistance. It has been hypothesized that cancer cells undergoing EMT acquire unique properties that resemble those of cancer stem cells (CSCs). These stem-like cells manifest enhanced DNA damage response (DDR) and DNA repair capacity, self-renewal, or chemoresistance. In contrast, functional experiments have shown that ZEB1 induces chemoresistance regardless of whether other EMT-related changes occur. ZEB1 has also been identified as an important regulator of DDR by the formation of a ZEB1/p300/PCAF complex and direct interaction with ATM kinase, which has been linked to radioresistance. Moreover, ATM can directly phosphorylate ZEB1 and enhance its stability. Downregulation of ZEB1 has also been shown to reduce the abundance of CHK1, an effector kinase of DDR activated by ATR, and to induce its ubiquitin-dependent degradation. In this perspective, we focus on the role of ZEB1 in the regulation of DDR and describe the mechanisms of ZEB1-dependent chemoresistance.

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Section: Interplay Between Micrornas Zeb1 and Dna Damage Responsementioning

confidence: 99%

ZEB1: A Critical Regulator of Cell Plasticity, DNA Damage Response, and Therapy Resistance

Drápela

Bouchal

Jolly

et al. 2020

Front. Mol. Biosci.

124

View full text Add to dashboard Cite

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“…Among these 8 lncRNAs, except for HAGLROS and TONSL-AS1, other lncRNAs have not been investigated thoroughly and were discovered as prognostic signatures for the rst time. HAGLROS is alncRNA with a length of 699 bp, was reported to involve in the progression of various cancers [29][30][31][32][33][34][35][36], including lung cancer, colorectal cancer, lymphoma, ovarian cancer, osteosarcoma, nasopharyngeal carcinoma, intrahepatic cholangiocarcinoma. HAGLROS regulates apoptosis and autophagy via PI3K/Akt/mTOR signaling pathway [29,31,37], miR-5095/ATG12 axis [36] or miR-100/ATG5 axis [31,38].…”

Section: Discussionmentioning

confidence: 99%

An 8-lncRNA signature predicts survival of triple-negative breast cancer patients without germline BRCA1/2 mutation

Liu

Dai

Zhu

et al. 2020

Preprint

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Background Triple-negative breast cancer (TNBC) is a particular breast cancer subtype with poor prognosis due to its aggressive biological behavior and strong heterogeneity. TNBC with germline BRCA1/2 mutation (gBRCAm) have higher sensitivity to DNA damaging agents including platinum-based chemotherapy and PARP inhibitors. But the treatment of TNBC without gBRCAm remains challenging. This study aimed to develop a long non-coding RNA (lncRNA) signature of TNBC patients without gBRCAm to improve risk stratification and optimize individualized treatment. Methods 98 TNBC patients without gBRCAm were acquired from The Cancer Genome Atlas (TCGA) database. The univariable Cox regression analysis and LASSO Cox regression model were applied to establish an lncRNA signature in the training cohort (N = 59). Then Kaplan–Meier survival curve and time-dependent ROC curve were used to validate the prognostic ability of the signature. The signature related mRNAs were identified using the Pearson correlation. Functional enrichment analysis of related mRNA was performed using the Metascape. The qPCR assay was performed to confirm the expressions and clinicopathological correlationsof two potential lncRNAs HAGLROS and TONSL-AS1 in 30 paired clinical triple-negative breast cancer samples without gBRCAm. Results We developed an 8-lncRNA signature in the training cohort including HAGLROS, AL139002.1, AL391244.2, AP000696.1, AL391056.1, AL513304.1, TONSL-AS1 and AL031008.1. In both the training and validation cohort, patients with higher risk scores showed significantly worse overall survival compared to those with lower risk scores(P = 0.00018 and P = 0.0068 respectively). 1, 5, 8-year AUC in the training cohort were 1.000, 1.000 and 0.908 respectively, in the validation cohort were 0.785, 0.790 and 0.892 respectively indicating that our signature has a good prognostic capacity. Signature related mRNA mainly enriched in terms include RNA metabolic process, DNA repair pathways, and so on. Two potential lncRNAs HAGLROS and TONSL-AS1 were found frequently overexpressed in TNBC without gBRCAm, and significantly associated with tumor grade and invasion. Conclusions We constructed a novel 8-lncRNA signaturewhich significantly associated with the overall survival of TNBC patients without gBRCAm. Among those 8lncRNAs, HAGLROS and TONSL-AS1 may be potential therapeutic targetswhich function needed further exploration.

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“…Among these 8 lncRNAs, except for HAGLROS and TONSL-AS1, other 6 lncRNAs have not been investigated thoroughly and were discovered as prognostic signatures for the rst time. HAGLROS is alncRNA with a length of 699 bp, was reported to involve in the progression of various cancers [29][30][31][32][33][34][35][36], including lung cancer, colorectal cancer, lymphoma, ovarian cancer, osteosarcoma, nasopharyngeal carcinoma, intrahepatic cholangiocarcinoma. HAGLROS regulates apoptosis and autophagy via PI3K/Akt/mTOR signaling pathway [29,31,37], miR-5095/ATG12 axis [36] or miR-100/ATG5 axis [31,38].…”

Section: Discussionmentioning

confidence: 99%

An 8-lncRNA Signature Predicts Survival of Triple-Negative Breast Cancer Patients Without Germline BRCA1/2 Mutation

Liu

Dai

Zhu

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Triple-negative breast cancer (TNBC) is a particular breast cancer subtype with poor prognosis due to its aggressive biological behavior and strong heterogeneity. TNBC with germline BRCA1/2 mutation (gBRCAm) have higher sensitivity to DNA damaging agents including platinum-based chemotherapy and PARP inhibitors. But the treatment of TNBC without gBRCAm remains challenging. This study aimed to develop a long non-coding RNA (lncRNA) signature of TNBC patients without gBRCAm to improve risk stratification and optimize individualized treatment.Methods: 98 TNBC patients without gBRCAm were acquired from The Cancer Genome Atlas (TCGA) database. The univariable Cox regression analysis and LASSO Cox regression model were applied to establish an lncRNA signature in the training cohort (N = 59). Then Kaplan–Meier survival curve and time-dependent ROC curve were used to validate the prognostic ability of the signature. The signature related mRNAs were identified using the Pearson correlation. Functional enrichment analysis of related mRNA was performed using the Metascape. The qPCR assay was performed to confirm the expressions and clinicopathological correlationsof two potential lncRNAs HAGLROS and TONSL-AS1 in 30 paired clinical triple-negative breast cancer samples without gBRCAm.Results:We developed an 8-lncRNA signature in the training cohort including HAGLROS, AL139002.1, AL391244.2, AP000696.1, AL391056.1, AL513304.1, TONSL-AS1 and AL031008.1. In both the training and validation cohort, patients with higher risk scores showed significantly worse overall survival compared to those with lower risk scores(P=0.00018 and P =0.0068 respectively). 1, 5, 8-year AUC in the training cohort were 1.000, 1.000 and 0.908 respectively, in the validation cohort were 0.785, 0.790 and 0.892 respectively indicating that our signature has a good prognostic capacity. Signature related mRNA mainly enriched in terms include RNA metabolic process, DNA repair pathways, and so on. Two potential lncRNAs HAGLROS and TONSL-AS1 were found frequently overexpressed in TNBC without gBRCAm, and significantly associated with tumor grade and invasion.Conclusions: We constructed a novel 8-lncRNA signaturewhich significantly associated with the overall survival of TNBC patients without gBRCAm. Among those 8lncRNAs, HAGLROS and TONSL-AS1 may be potential therapeutic targetswhich function needed further exploration.

show abstract

LncRNAs as Regulators of Autophagy and Drug Resistance in Colorectal Cancer

Cited by 92 publications

References 199 publications

ZEB1: A Critical Regulator of Cell Plasticity, DNA Damage Response, and Therapy Resistance

ZEB1: A Critical Regulator of Cell Plasticity, DNA Damage Response, and Therapy Resistance

An 8-lncRNA signature predicts survival of triple-negative breast cancer patients without germline BRCA1/2 mutation

An 8-lncRNA Signature Predicts Survival of Triple-Negative Breast Cancer Patients Without Germline BRCA1/2 Mutation

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