The transcribed pseudogene RPSAP52 enhances the oncofetal HMGA2-IGF2BP2-RAS axis through LIN28B-dependent and independent let-7 inhibition

Oliveira-Mateos, Cristina; Sánchez‐Castillo, Anaís; Soler, Marta; Obiols-Guardia, Aida; Piñeyro, David; Boqué-Sastre, Raquel; Calleja-Cervantes, María Eréndira; Moura, Manuel Castro de; Martínez-Cardús, Anna; Rubio, Teresa; Pelletier, Joffrey; Martínez-Iniesta, María; Herrero-Martín, David; Tirado, Óscar M.; Gentilella, Antonio; Villanueva, Alberto; Esteller, Manel; Farré, Lourdes; Guil, Sònia

doi:10.1038/s41467-019-11910-6

Cited by 43 publications

(40 citation statements)

References 73 publications

(84 reference statements)

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“…However, compared with other members of lncRNAs, transcribed pseudogenes-derived lncRNAs have not been paid attention previously. Recent studies have demonstrated that transcribed pseudogenederived lncRNAs play important roles in multiple biological processes, such as cell proliferation, cell cycle, cell migration and cell death (Lai et al, 2019;Oliveira-Mateos et al, 2019;Varesio et al, 2019).…”

Section: Origination and Classification Of Pseudogenes And Pseudogenementioning

confidence: 99%

Pseudogene-Derived lncRNAs and Their miRNA Sponging Mechanism in Human Cancer

Lou

Ding

2020

Front. Cell Dev. Biol.

120

111

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Section: Origination and Classification Of Pseudogenes And Pseudogenementioning

confidence: 99%

Pseudogene-Derived lncRNAs and Their miRNA Sponging Mechanism in Human Cancer

Lou

Ding

2020

Front. Cell Dev. Biol.

120

111

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“…Here, we show a complex picture of antisense transcription in HMGA2 gene, increasing the number of molecules possibly involved in HMGA2 expression regulation, while HMGA1 locus exhibited a lower antisense transcription. Among antisense transcription genes in HMGA2 locus, we have found the previously characterized head-to-head natural antisense lncRNA RPSAP52 (33)(34)(35). In this study, in addition to RPSAP52, we provide, for the first time to our knowledge, evidences for the existence of previously unknown natural antisense lncRNAs within HMGA2 gene with a function in HMGA2 expression regulation and neoplastic transformation.…”

Section: Discussionmentioning

confidence: 61%

“…Indeed, we observed three independent TSS in antisense orientation relative to HMGA2 transcription, which promoted the transcription of three genes, annotated in FANTOM-CAT as "Other RNAs" (RPSAP52 and RP11-366L20.2, also named HMGA2-AS1), and "Enhancer lncRNA" (RP11-366L20.3) ( Figure 1). The first natural antisense gene present in the HMGA2 locus, named RPSAP52 (ENSG00000241749), includes a head-tohead divergent to 5 ′ HMGA2 antisense RNA ( Figure 1) and has already been described to be involved in HMGA2 gene expression regulation (33)(34)(35). The second natural antisense gene, originally named RP11-366L20.2 (uncharacterized LOC100129940: ENSG00000197301) and now HMGA2-AS1 according to HGNC (HUGO Gene Nomenclature Committee), is located in the first part of the HMGA2 third intron and has not been investigated so far, as well as the third gene, RP11-366L20.3 (ENSG00000256083.…”

Section: Hmga1 and Hmga2 Loci Contain Several Natural Antisense Rnasmentioning

confidence: 99%

“…The expression of these two genes is orchestrated both at transcriptional and post-transcriptional level (28,31,32). In addition, very recently, two research groups revealed that ribosomal protein SA pseudogene (RPSAP52) antisense lncRNA at the 5 ′ of HMGA2 gene is able to modulate HMGA2 both at transcriptional (33) and post-transcriptional level (34,35).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

HMGA2 Antisense Long Non-coding RNAs as New Players in the Regulation of HMGA2 Expression and Pancreatic Cancer Promotion

et al. 2020

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Background: Natural antisense long non-coding RNAs (lncRNAs) are regulatory RNAs transcribed from the opposite strand of either protein coding or non-coding genes, able to modulate their own sense gene expression. Hence, their dysregulation can lead to pathologic processes. Cancer is a complex class of diseases determined by the aberrant expression of a variety of factors, among them, the oncofetal chromatin architectural proteins High Mobility Group A (HMGA) modulate several cancer hallmarks. Thus, we decided to investigate the presence of natural antisense lncRNAs in HMGA1 and HMGA2 loci, and their possible involvement in gene expression regulation. Methods: We used FANTOM5 data resources, FANTOM-CAT genome browser and Zenbu visualization tool, which employ 1,829 human CAGE and RNA-sequencing libraries, to determine expression, ontology enrichment, and dynamic regulation of natural antisense lncRNAs in HMGA1 and HMGA2 loci. We then performed qRT-PCR in different cancer cell lines to validate the existence of HMGA2-AS1 transcripts. We depleted HMGA2-AS1 transcripts with siRNAs and investigated HMGA2 expression by qRT-PCR and western blot analyses. Moreover, we evaluated cell viability and migration by MTS and transwell assays, and EMT markers by qRT-PCR and immunofluorescence. Furthermore, we used bioinformatics approaches to evaluate HMGA2 and HMGA2-AS1 correlation and overall survival in tumor patients. Results: We found the presence of a promoter-associated lncRNA (CATG00000088127.1) in the HMGA1 gene and three antisense genes (RPSAP52, HMGA2-AS1, and RP11-366L20.3) in the HMGA2 gene. We studied the uncharacterized HMGA2-AS1 transcripts, validating their existence in cancer cell lines and observing a positive correlation between HMGA2 and HMGA2-AS1 expression in a cancer-derived patient dataset. We showed that HMGA2-AS1 transcripts positively modulate HMGA2 expression and migration properties of PANC1 cells through HMGA2. In addition, Kaplan-Meier analysis showed that high level of HMGA2-AS1 is a negative prognostic factor in pancreatic cancer patients. Ros et al. HMGA2 Regulation by HMGA2-AS1 Conclusions: Our results describe novel antisense lncRNAs associated with HMGA1 and HMGA2 genes. In particular, we demonstrate that HMGA2-AS1 is involved in the regulation of its own sense gene expression, mediating tumorigenesis. Thus, we highlight a new layer of complexity in the regulation of HMGA2 expression, providing new potential targets for cancer therapy.

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“…Pseudogenes can interact with parental genes or other gene loci, leading to alterations in sequences and/or transcriptional activities. Pseudogene-derived RNAs play multifaceted roles in posttranscriptional regulation as antisense RNAs, endogenous small-interference RNAs, and competing endogenous RNAs that govern gene expression related to cancer progression, metastasis, and drug resistance in multiple tumors [5][6][7][8][9]. For example, recent research has revealed that the pseudogene KRT19P3 suppresses gastric cancer growth and metastasis through the COPS7Amediated NF-κB pathway [7].…”

Section: Introductionmentioning

confidence: 99%

Pseudogene KRT17P3 Drives Cisplatin Resistance of Human NSCLC Cells by Modulating miR-497-5p/mTOR

Hou

Zhou

Xia

et al. 2020

Preprint

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Background: Chemoresistance is a major obstacle in non-small-cell lung cancer (NSCLC) treatment. The pseudogene KRT17P3 has been shown to be up-regulated in lung cancer tissues from patients with cisplatin resistance. However, its molecular mechanism in promoting chemoresistance has not been elucidated.Methods: Real-time PCR was performed to evaluate KRT17P3 levels in plasma samples collected from 30 cisplatin-resistance patients and 32 cisplatin-sensitive patients. KRT17P3 was overexpressed or knocked down in A549 and SK-MES-1 NSCLC cells to evaluate the effects of KRT17P3 on the in vitro and in vivo resistance of NSCLC to cisplatin. Cell Counting Kit 8, Annexin V/propidium iodide staining, and PARP-1 cleavage assays were performed to evaluate cell viability and apoptosis. Dual luciferase reporter, RNA immunoprecipitation, Western blot assays, and rescue experiments were used to evaluate the functional interaction of KRT17P3, miR-497-5p and mTOR.Results: Our results demonstrate that KRT17P3 overexpression in cultured NSCLC cells increases cell viability and decreases apoptosis upon cisplatin treatment, while KRT17P3 knockdown has the opposite effect. KRT17P3 overexpression promotes NSCLC tumor growth upon in cisplatin-treated xenografted mice. Mechanistically, KRT17P3 acts as a molecular sponge for miR-497-5p and relieves the binding of miR-497-5p to its target gene mTOR. Rescue experiments validated the functional interaction among KRT17P3, miR497-5p, and mTOR. Moreover, the plasma level of KRT17P3 is up-regulated in cisplatin-resistance patients.Conclusions: Our findings indicate that KRT17P3/miR497-5p/mTOR regulates the chemosensitivity of NSCLC, suggesting a potential therapeutic target for cisplatin-resistant NSCLC patients. KRT17P3 may be a potential peripheral blood marker of NSCLC patients resistant to cisplatin.

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The transcribed pseudogene RPSAP52 enhances the oncofetal HMGA2-IGF2BP2-RAS axis through LIN28B-dependent and independent let-7 inhibition

Cited by 43 publications

References 73 publications

Pseudogene-Derived lncRNAs and Their miRNA Sponging Mechanism in Human Cancer

Pseudogene-Derived lncRNAs and Their miRNA Sponging Mechanism in Human Cancer

HMGA2 Antisense Long Non-coding RNAs as New Players in the Regulation of HMGA2 Expression and Pancreatic Cancer Promotion

Pseudogene KRT17P3 Drives Cisplatin Resistance of Human NSCLC Cells by Modulating miR-497-5p/mTOR

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