miR-424(322)/503 is a breast cancer tumor suppressor whose loss promotes resistance to chemotherapy

Rodríguez-Barrueco, Ruth; Nekritz, Erin A.; Bertucci, François; Yu, Jiyang; Sanchez-Garcia, Félix; Zeleke, Tizita; Gorbatenko, Andrej; Birnbaum, Daniel; Ezhkova, Elena; Cordon‐Cardo, Carlos; Finetti, Pascal; Llobet‐Navas, David; Silva, José M.

doi:10.1101/gad.292318.116

Cited by 81 publications

(57 citation statements)

References 85 publications

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“…It is possible that miR-424 regulates other aspects besides the effects on HPV genome amplification via modulation of the ATR DNA damage pathway. Recent studies have shown that miR-424 also regulates BCL-2 and insulin-like growth factor 1, suggesting that it has tumor suppressor activities (33). In contrast to our observations with HPV, the levels of miR-424 are increased in EBV-positive, diffuse, large B cell lymphomas (34).…”

Section: Discussioncontrasting

confidence: 72%

Suppression of MicroRNA 424 Levels by Human Papillomaviruses Is Necessary for Differentiation-Dependent Genome Amplification

Hong

Cheng

Songock

et al. 2017

J Virol

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High-risk human papillomaviruses (HPVs) link their life cycle to epithelial differentiation and require activation of DNA damage pathways for efficient replication. HPVs modulate the expression of cellular transcription factors, as well as cellular microRNAs (miRNAs) to control these activities. One miRNA that has been reported to be repressed in HPV-positive cancers of the cervix and oropharynx is miR-424. Our studies show that miR-424 levels are suppressed in cell lines that stably maintain HPV 31 or 16 episomes, as well as cervical cancer lines that contain integrated genomes such as SiHa. Introduction of expression vectors for miR-424 reduced both the levels of HPV genomes in undifferentiated cells and amplification upon differentiation. Our studies show that the levels of two putative targets of miR-424 that function in DNA damage repair, CHK1 and Wee1, are suppressed in HPV-positive cells, providing an explanation for why this microRNA is targeted in HPV-positive cells.IMPORTANCE We describe here for the first time a critical role for miR-424 in the regulation of HPV replication. HPV E6 and E7 proteins suppress the levels of miR-424, and this is important for controlling the levels of CHK1, which plays a central role in viral replication.KEYWORDS amplification, HPV, microRNA, DNA damage repair, CHK1, check point H uman papillomaviruses (HPVs) are the causative agents of cervical and other anogenital cancers (1). HPVs are classified as either high-risk types (such as HPV16, -18, -31, and -35), which are associated with the development of cancers of the anogenital tract and oropharynx or low-risk groups (such as HPV6 and HPV11) that are infrequently detected in malignancies. HPV virions infect cells in the basal layer of stratified epithelia to establish persistent infections. In infected basal cell cells, genomes are maintained as low-copy episomes that replicate in synchrony with cellular chromosomes. Productive viral replication or amplification, however, occurs only upon epithelial differentiation in suprabasal layers (2, 3). High-risk HPVs encode two major oncoproteins, E6 and E7, that play critical roles in cell transformation and provide important regulatory functions during the differentiation-dependent life cycle. One major target of E6 is the E3 ligase E6-associated protein E6AP, which forms trimeric complexes with p53, resulting in its rapid turnover (4-6). Similarly, E7 binds and induces the degradation of pRb, which results in the constitutive activation of E2F family members, leading to altered cell cycle control and differentiation (7,8). Additional important targets of these viral proteins include the ataxia telangiectasia-mutated (ATM) and the ATM and Rad3-related (ATR) DNA repair pathways that play critical roles in HPV replication (9, 10). E6 and E7 regulate these pathways by altering the expression

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Section: Discussioncontrasting

confidence: 72%

Suppression of MicroRNA 424 Levels by Human Papillomaviruses Is Necessary for Differentiation-Dependent Genome Amplification

Hong

Cheng

Songock

et al. 2017

J Virol

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“…Loss of miR-424 was associated with aggressiveness of breast cancers in human. Knockout of miR-424 promoted breast tumorigenesis in mice [40]. miR-4286 was also highly expressed in chemosensitive tumors [16].…”

Section: Circrnaome Of Ebv Sponged Mirnas Of Host Cells Involved In Mmentioning

confidence: 99%

Epstein-Barr virus circRNAome as host miRNA sponge regulates virus infection, cell cycle, and oncogenesis

Qiao

Zhao

et al. 2019

Bioengineered

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Epstein-Barr virus (EBV) is an oncogenic virus that infects more than 90% of the world's population. The proteins and miRNAs encoded by EBV are involved in multiple human malignancies. Recently R-resistance RNA-seq demonstrated that EBV-encoded circular RNAs. The current research aims to explore their functions in EBV-associated malignancies. Total 56 miRNAs were sponged by circRNAome. 24 and 9 in EBV host B and epithelial cells out of 56 miRNAs were detectable by miRNAseq. 18 and 5 miRNAs were down-regulated in both types of host cells, respectively, after EBV infection. The network between five miRNAs and their targets included 1414 genes, 1419 nodes, and 2423 edges. These targets were enriched in multiple categories, and most of them were up-regulated in EBV-infected cells. These data represented the first report that EBV circRNAs could sponge the miRNAs to promote the up-regulated expression of their targets, involving in malignancies associated with EBV.

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“…Nakashima et al [32] demonstrated a regulatory mechanism of angiogenesis in the aged skin from miRNAs, in particular showing that a decreased mir-424 expression and increased levels of MEK1 (mitogen-activated protein kinase) or cyclin E1 may cause abnormal cell proliferation. It has also been reported that microRNAs play an important role in the case of breast cancer, and in particular the loss of miR-424(322)/503 was associated with poor prognosis characteristics such as a high-grade tumours, a larger pathological tumour size, a triple-negative status, and strong cell proliferation ( KI67 mRNA expression) [33]. These observations leave at least the doubt that cytokine produced by cancer cells can determine the common dysfunction of microRNAs.…”

Section: Discussionmentioning

confidence: 99%

The Influence of Breast Cancer on the Distribution of Cherry Angiomas on the Anterior Thoracic Wall: A Case Series Study

et al. 2018

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Background/Aims: Cherry angiomas (CAs) are one of the most common vascular manifestations of the skin. By and large, these benign lesions often only represent an aesthetic problem. In the literature, few authors have focused on the pathogenesis of these lesions, and some risk factors have been identified, such as the presence of cutaneous and non-skin neoplasias. In this study, the correlation between the distribution of CAs and breast cancer was investigated. Methods: We carried out a study whereby 50 women with unilateral breast cancer and the presence of CAs on the anterior thoracic wall were evaluated, with a particular focus on the difference in the number of CAs between the two haemithoraces. The data was elaborated using the Wilcoxon signed-rank test in order to evaluate whether there was a statistical significance in the distribution of CAs. Results: In 31 patients we found that the number of CAs was greater on the cancerous breast than on the contralateral one (p value <0.0001). This was confirmed both in the group of patients suffering from ductal breast cancer and in the group with early invasive breast tumours. Conclusion: It is not clear whether CAs develop prior to or following breast cancer, indicating the possibility that this cutaneous manifestation could take on a predictive, prognostic development or represent only an epiphenomenon. Further in-depth studies into the pathogenesis of CAs and the relationship with breast cancer could lead to noteworthy diagnostic-therapeutic advances.

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miR-424(322)/503 is a breast cancer tumor suppressor whose loss promotes resistance to chemotherapy

Cited by 81 publications

References 85 publications

Suppression of MicroRNA 424 Levels by Human Papillomaviruses Is Necessary for Differentiation-Dependent Genome Amplification

Suppression of MicroRNA 424 Levels by Human Papillomaviruses Is Necessary for Differentiation-Dependent Genome Amplification

Epstein-Barr virus circRNAome as host miRNA sponge regulates virus infection, cell cycle, and oncogenesis

The Influence of Breast Cancer on the Distribution of Cherry Angiomas on the Anterior Thoracic Wall: A Case Series Study

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