The well-accepted notion that gene amplification contributes to increased expression still remains, after all these years, a reasonable but unproven assumption

Jia, Yuping; Chen, Lichan; Jia, Qidong; Dou, Xixi; Xu, Nuo; Liao, D. Joshua

doi:10.4103/1477-3163.182809

Cited by 23 publications

(23 citation statements)

References 56 publications

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“…On the other hand, the analysis of SCNAs in FOXD2-AS1 and LINC00968 show that FOXD2-AS1 is not signi cantly focally ampli ed or deleted, but LINC00968 is signi cantly focally ampli ed in invasive breast carcinoma. Ampli cation is a genetic mechanism of overexpression that is a well-accepted concept in cancer genetics (44). Ampli cation of FOXD2-AS1 might be played a role in the breast cancer tumorigenesis, but it is thought that ampli cation might not relate to the low expression of LINC00968 in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

The Possible Roles of Long Non-Coding RNAs FOXD2-AS1 and LINC00968 in Breast Cancer: Case-Control Study and in Silico Analysis

Arabpour¹,

Layeghi²,

Majidzadeh‐A³

et al. 2020

Preprint

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Background: Breast Cancer (BC) is the most common cancer in women worldwide. Long non-coding RNAs (lncRNAs) are regulatory non-coding transcripts and longer than 200 nucleotides. lncRNAs can affect many biological and pathological processes and dysregulation of them is related and studied in many human diseases like, cancers. We performed this study to evaluate the probable functions of lncRNAs FOXD2-AS1 and LINC00968 in breast cancer. Methods: The tumor tissue and adjacent non-tumor tissue specimens of luminal A and B breast cancer (the most frequent subtypes of breast cancer) were used to analyze the expression of these two lncRNAs, using the qRT-PCR technique. Furthermore, two luminal A breast cancer cell lines, MCF7 and T47D, were used to evaluate the expression of FOXD2-AS1 and LINC00968 compared with control breast cell line, MCF10A. Because of the luminal subtypes are the most frequent subtypes of breast cancer and also the most common subtypes among breast cancer patients, the present study was generally focused on the luminal and breast cancer. Also, some in silico analyses were done according to some databases and software for better understanding about the potential functions of mentioned lncRNAs in breast cancer. Results: Our data indicated the significant upregulation and downregulation of FOXD2-AS1 and LINC00968, respectively, in tumor tissues and breast cancer cell lines (MCF7, T47D). The bioinformatic analyses confirmed the experimental results. FOXD2-AS1 expression was positively associated with p53 protein and LINC00968 expression was negatively associated with tumor stage and lymph node metastasis. According to our findings, LINC00968 might be function as a tumor suppressor gene in breast cancer and this lncRNA might function in some cellular signaling pathways, like PI3K/Akt and Ras signaling pathways based on the co-expressed genes, but more investigations are required. Conclusions: The two mentioned lncRNAs might play roles in breast cancer pathogenesis but more experimental studies are needed to explore the mechanisms of the functions of these two lncRNAs in breast cancer.

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Section: Discussionmentioning

confidence: 99%

The Possible Roles of Long Non-Coding RNAs FOXD2-AS1 and LINC00968 in Breast Cancer: Case-Control Study and in Silico Analysis

Arabpour¹,

Layeghi²,

Majidzadeh‐A³

et al. 2020

Preprint

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“…Previous studies have not shown whether tumors carrying amplified RRM2B have increased RRM2B expression, which might directly impact its role in cancer. Multiple studies have observed that gene amplifications do not always lead to increased expression [31]. Thus, to confirm increased expression, we used mRNA expression data from three TCGA studies (OV, BRCA, HNSC), and found that tumors with gains and amplifications had significantly increased RRM2B mRNA expression in all three cancer types studied (Supplementary…”

Section: Tumors With Rrm2b Amplifications Exhibit Increased Rrm2b Expmentioning

confidence: 99%

RRM2Bis frequently amplified across multiple tumor types: non-oncogenic addiction and therapeutic opportunities

Iqbal

Demidova

Serrao

et al. 2020

Preprint

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RRM2B plays a crucial role in DNA replication, repair and oxidative stress. While germline RRM2B mutations have been implicated in mitochondrial disorders, its relevance to cancer has not been established. Here, using TCGA data, we investigated RRM2B alterations in cancer. We found that RRM2B is highly amplified in multiple tumor types, particularly in MYC-amplified tumors, and is associated with increased RRM2B mRNA expression. We also observed that the chromosomal region 8q22.3–8q24, is amplified in multiple tumors, and includes RRM2B, MYC along with several other cancer-associated genes. An analysis of genes within this 8q-amplicon showed that cases that have both RRM2B-amplified along with MYC have a distinct pattern of amplification compared to unaltered cases or cases that have amplifications in RRM2B or MYC only. These other 8q-proteins were shown to interact functionally within the RRM2B network of DNA repair, hypoxia and apoptosis regulating proteins. Notably, RRM2B-amplified tumors are characterized by mutation signatures of defective DNA repair and oxidative stress, and in some cancers also associated with poor clinical outcome. These findings suggest that some cancers may require RRM2B for cellular survival, providing novel therapeutic opportunities in these cancers.

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“…The involvement of highly conserved and ubiquitous transmembrane tyrosine kinase receptors, namely fibroblast growth factor receptors (FGFRs), in tumorigenesis, cell fate determination, survival, motility, angiogenesis, and malignantization of tumor cells, as well as in reduced sensitivity to anticancer therapeutics and poor prognosis is extensively documented [5]. Notably, genetic alterations in FGFR1, such as amplification or an increase in gene copy number, are positively correlated with overexpression and are more prevalent than genetic aberrations in FGFR2, FGFR3, and FGFR4 [5,6]. Hence, Lehnen et al, studying the role of the FGFR1 gene copy number and expression pattern in patients with PDAC, suggested that the association between FGFR1 amplification, mRNA or protein expression, and the proliferative potential of PDAC cells can be exploited for therapeutic purposes using FGFR1 inhibitors [7].…”

Section: Introductionmentioning

confidence: 99%

Targeted PARP Inhibition Combined with FGFR1 Blockade is Synthetically Lethal to Malignant Cells in Patients with Pancreatic Cancer

Lai

Bamodu

Chen

et al. 2020

Cells

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The role and therapeutic promise of poly-ADP ribose polymerase (PARP) inhibitors in anticancer chemotherapy are increasingly being explored, particularly in adjuvant or maintenance therapy, considering their low efficacy as monotherapy agents and their potentiating effects on concurrently administered contemporary chemotherapeutics. Against the background of increasing acquired resistance to FGFR1 inhibitors and our previous work, which partially demonstrated the caspase-3/PARP-mediated antitumor and antimetastatic efficacy of PD173074, a selective FGFR1 inhibitor, against ALDH-high/FGFR1-rich pancreatic ductal adenocarcinoma (PDAC) cells, we investigated the probable synthetic lethality and therapeutic efficacy of targeted PARP inhibition combined with FGFR1 blockade in patients with PDAC. Using bioinformatics-based analyses of gene expression profiles, co-occurrence and mutual exclusivity, molecular docking, immunofluorescence staining, clonogenicity, Western blotting, cell viability or cytotoxicity screening, and tumorsphere formation assays, we demonstrated that FGFR1 and PARP co-occur, form a complex, and reduce survival in patients with PDAC. Furthermore, FGFR1 and PARP expression was upregulated in FGFR1 inhibitor (dasatinib)-resistant PDAC cell lines SU8686, MiaPaCa2, and PANC-1 compared with that in sensitive cell lines Panc0403, Panc0504, Panc1005, and SUIT-2. Compared with the limited effect of single-agent olaparib (PARP inhibitor) or PD173074 on PANC-1 and SUIT-2 cells, low-dose combination (olaparib + PD173074) treatment significantly, dose-dependently, and synergistically reduced cell viability, upregulated cleaved PARP, pro-caspase (CASP)-9, cleaved-CASP9, and cleaved-CASP3 protein expression, and downregulated Bcl-xL protein expression. Furthermore, combination treatment markedly suppressed the clonogenicity and tumorsphere formation efficiency of PDAC cells regardless of FGFR1 inhibitor-resistance status and enhanced RAD51 and γ-H2AX immunoreactivity. In vivo studies have shown that both early and late initiation of combination therapy markedly suppressed tumor xenograft growth and increase in weight, although the effect was more pronounced in the early initiation group. In conclusion, FGFR1 inhibitor-resistant PDAC cells exhibited sensitivity to PD173074 after olaparib-mediated loss of PARP signaling. The present FGFR1/PARP-mediated synthetic lethality proof-of-concept study provided preclinical evidence of the feasibility and therapeutic efficacy of combinatorial FGFR1/PARP1 inhibition in human PDAC cell lines.

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The well-accepted notion that gene amplification contributes to increased expression still remains, after all these years, a reasonable but unproven assumption

Cited by 23 publications

References 56 publications

The Possible Roles of Long Non-Coding RNAs FOXD2-AS1 and LINC00968 in Breast Cancer: Case-Control Study and in Silico Analysis

The Possible Roles of Long Non-Coding RNAs FOXD2-AS1 and LINC00968 in Breast Cancer: Case-Control Study and in Silico Analysis

RRM2Bis frequently amplified across multiple tumor types: non-oncogenic addiction and therapeutic opportunities

Targeted PARP Inhibition Combined with FGFR1 Blockade is Synthetically Lethal to Malignant Cells in Patients with Pancreatic Cancer

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