Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation

Napoli, Marco; Li, Xiaobo; Ackerman, Hayley D.; Deshpande, Avani A.; Barannikov, Ivan; Pisegna, Marlese A.; Bedrosian, Isabelle; Mitsch, Jürgen; Quinlan, P; Thompson, Alastair; Rajapakshe, Kimal I.; Coarfa, Cristian; Gunaratne, Preethi H.; Marchion, Douglas C.; Magliocco, Anthony M.; Tsai, Kenneth Y.; Flores, Elsa R.

doi:10.1038/s41467-020-18973-w

Cited by 13 publications

(10 citation statements)

References 75 publications

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“…WDR26 is a component of the CTLH complex that is mutated or upregulated in many solid cancers [ 9 ]. WDR26 has not been implicated in blood cancers, yet its significance as therapeutic target in carcinomas has been recognized [ 10 ]. MTF2, an accessory unit of the PRC2 complex involved in gene repression and growth promotion of various cancers [ 11 ], is a validated molecular target in AML [ 12 ].…”

Section: To the Editormentioning

confidence: 99%

WDR26 and MTF2 are therapeutic targets in multiple myeloma

et al. 2021

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Unbiased genetic forward screening using retroviral insertional mutagenesis in a genetically engineered mouse model of human multiple myeloma may further our understanding of the genetic pathways that govern neoplastic plasma cell development. To evaluate this hypothesis, we performed a tumor induction study in MYC-transgenic mice infected as neonates with the Moloney-derived murine leukemia virus, MOL4070LTR. Next-generation DNA sequencing of proviral genomic integration sites yielded rank-ordered candidate tumor progression genes that accelerated plasma cell neoplasia in mice. Rigorous clinical and biological validation of these genes led to the discovery of two novel myeloma genes: WDR26 (WD repeat-containing protein 26) and MTF2 (metal response element binding transcription factor 2). WDR26, a core component of the carboxy-terminal to LisH (CTLH) complex, is overexpressed or mutated in solid cancers. MTF2, an ancillary subunit of the polycomb repressive complex 2 (PRC2), is a close functional relative of PHD finger protein 19 (PHF19) which is currently emerging as an important driver of myeloma. These findings underline the utility of genetic forward screens in mice for uncovering novel blood cancer genes and suggest that WDR26-CTLH and MTF2-PRC2 are promising molecular targets for new approaches to myeloma treatment and prevention.

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Section: To the Editormentioning

confidence: 99%

WDR26 and MTF2 are therapeutic targets in multiple myeloma

et al. 2021

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“…The specific mechanism by which NOLC1 contributed to tumorigenesis remains unclear. Intriguingly, it was recently reported that lncRNAs (TROLL-2 and TROLL-3) could counteract the interaction between WDR26 and NOLC1, while promoting the combination of WDR26 and AKT to activate the PI3K/AKT pathway in lung cancer cells, human breast carcinoma cells, and human melanoma cell lines [ 16 ]. PI3K/AKT pathway is dysregulated in various cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of NOLC1 Inhibits PI3K-AKT Pathway to Improve the Poor Prognosis of Esophageal Carcinoma

Kong

Shang

Diao

et al. 2021

Journal of Oncology

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Objective. Esophageal carcinoma (ESCA) is a common malignant gastrointestinal tumor. The abnormal expression of NOLC1 is involved in the tumorigenesis of various human tumors, whereas the function and mechanism of NOLC1 in ESCA remain unclear. In this study, we explored the relationship between NOLC1 and poor prognosis of ESCA, and its role and mechanism in the occurrence of ESCA. Methods. The NOLC1 expression in ESCA tissues and cell lines was determined by qRT-PCR, immunohistochemistry, or western blot. The Kaplan–Meier method was conducted to estimate the overall survival. Cox regression analysis was carried out to examine the association between patient characteristics and prognosis. A recombined lentiviral vector containing NOLC1 was applied for transfecting ESCA cells (Eca109 and TE-13) and established a stable cell line with low NOLC1 expression or high NOLC1 expression, in the absence or presence of PI3K inhibitor (LY294002) treatment. Cell proliferation, apoptosis rate, invasion ability, migration ability, and PI3K/AKT pathway were detected by CCK8 assay, flow cytometry, Transwell assay, wound-healing assay, and western blot. Results. NOLC1 overexpression was observed in ESCA tissues and ESCA cell lines (EC9706, Eca109, TE-13, Kyse170, T.TN) compared with adjacent normal tissues and normal esophageal cell line HEEC. NOLC1 overexpression was markedly associated with bigger tumor size, lymph node metastasis, and advanced TNM stage. Patients with NOLC1 overexpression have shorter overall survival than that of those with low NOLC1 expression. NOLC1 overexpression was considered to be an independent poor prognostic factor affecting overall survival. NOLC1 knockdown inhibited proliferation, migration, invasion, and cyclin B1 expression and promoted the apoptosis and cleaved-caspase-3 expression of Eca109 and TE-13 cells. NOLC1 overexpression accelerated proliferation, migration, invasion, and cyclin B1 expression and inhibited the apoptosis and cleaved-caspase-3 expression of ESCA cells via activating PI3K/AKT pathway. Rescue experiments showed that PI3K inhibitor (LY294002) could reverse the phenomenon caused by NOLC1 overexpression. Conclusion. NOLC1 may be a marker for poor prognosis. It can participate in the occurrence and development of ESCA via the PI3K/AKT pathway.

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“…Conversely, the coding gene GATA3 has a wide expression pattern in patients and breast cancer cell lines, as observed by RNA-Seq analysis. As previous studies have demonstrated, mRNAs tend to have less tissue-and stagespecific expression 41,58,59 in contrast to lncRNAs, which tend to have more tissue-specific 19,60,61 and stage-specific expression in disease, which is one of the main reasons lncRNAs have been proposed as molecular biomarkers in cancer. 16,62,63 Alternatively, results by receiver operating characteristic curve showed that GATA3 had sensitivity of 52.4% and specificity of 73.9% with an AUC of 0.60 in RT-qPCR expression analyses; the results suggest that GATA3 mRNA expression has low ability to distinguish responders from nonresponders to NAC due to its low sensitivity.…”

Section: Contreras-mentioning

confidence: 96%

Transcriptome Analysis Identifies GATA3-AS1 as a Long Noncoding RNA Associated with Resistance to Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer Patients

Contreras-Espinosa

Alcaraz

Rosa-Velázquez

et al. 2021

The Journal of Molecular Diagnostics

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Breast cancer is one of the leading causes of mortality in women worldwide, and neoadjuvant chemotherapy has emerged as an option for the management of locally advanced breast cancer. Extensive efforts have been made to identify new molecular markers to predict the response to neoadjuvant chemotherapy. Transcripts that do not encode proteins, termed long noncoding RNAs (lncRNAs), have been shown to display abnormal expression profiles in different types of cancer, but their role as biomarkers in response to neoadjuvant chemotherapy has not been extensively studied. Herein, lncRNA expression was profiled using RNA sequencing in biopsies from patients who subsequently showed either response or no response to treatment. The GATA3-AS1 Q10 transcript was overexpressed in the nonresponder group and was the most stable feature when performing selection in multiple random forest models. GATA3-AS1 was experimentally validated by RT-qPCR Q11 in an extended group of 68 patients. Expression analysis confirmed that GATA3-AS1 is overexpressed primarily in patients who were nonresponsive to neoadjuvant chemotherapy, with a sensitivity of 92.9%, a specificity of 75.0%, and an area under the curve of approximately 0.90, as measured by receiver operating characteristic curve analysis. The statistical model was based on luminal B-like patients and adjusted by menopausal status and phenotype (odds ratio, 37.49; 95% CI, 6.74e208.42; P Z 0.001); GATA3-AS1 was established as an independent predictor of response. Thus, lncRNA GATA3-AS1 is proposed as a potential predictive biomarker of nonresponse to neoadjuvant chemotherapy. Q12

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Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation

Cited by 13 publications

References 75 publications

WDR26 and MTF2 are therapeutic targets in multiple myeloma

WDR26 and MTF2 are therapeutic targets in multiple myeloma

Knockdown of NOLC1 Inhibits PI3K-AKT Pathway to Improve the Poor Prognosis of Esophageal Carcinoma

Transcriptome Analysis Identifies GATA3-AS1 as a Long Noncoding RNA Associated with Resistance to Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer Patients

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