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LncRNA related to enzalutamide treatment sensitivity and application of lncRNA to prostate cancer treatment by enzalutamide

A technology for enzalutamide and prostate cancer, which is applied to lncRNA and its application in the treatment of prostate cancer with enzalutamide, which can solve problems such as affecting the level of protein encoded by target genes and biological functions.

Inactive Publication Date: 2019-10-08
THE FIRST AFFILIATED HOSPITAL OF ANHUI MEDICAL UNIV
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  • Abstract
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Problems solved by technology

In addition, increasing evidence shows that lncRNAs can determine cellular processes through post-translational mechanisms, and can also affect mRNA translation by interacting with RNA-binding proteins (RBPs), thereby affecting the protein levels and biological functions encoded by target genes.

Method used

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  • LncRNA related to enzalutamide treatment sensitivity and application of lncRNA to prostate cancer treatment by enzalutamide
  • LncRNA related to enzalutamide treatment sensitivity and application of lncRNA to prostate cancer treatment by enzalutamide
  • LncRNA related to enzalutamide treatment sensitivity and application of lncRNA to prostate cancer treatment by enzalutamide

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Experimental program
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Effect test

Embodiment 1

[0028] Detection of sensitivity of Lnc-OPHN1-5 to regulate CRPC Enz:

[0029] Test materials: (1) Cell lines, inhibitors and antibodies: including EnzR1-C4-2 and EnzR2-C4-2B cells, cells were cultured in RPMI medium with 10 μM and 20 μM Enz added; GAPDH (sc-47724), AR(N-20), hnRNPA1(sc-32301), hnRNPA / B(sc-376411), hnRNPK(sc-28380) and HUR(sc-5261) antibodies were purchased from Santa Cruz Biotechnology (Dallas, Tx, USA); Lnc - OPHN1-5 and AR-specific biotin were purchased from Integrated DNA Technologies Company (IDT, Skokie, Illinois, USA);

[0030] (2) Plasmid and lentivirus packaging: The plasmids used are shown in Table 1, and they were packaged together with psAX2 packaging plasmid and pMD2G envelope plasmid, and were co-transfected into 293T cells by standard calcium chloride transfection method, 48 Hours later, the lentiviral supernatant was collected and stored in a -80°C refrigerator for later use, and the stable expression of pLKO.1 was screened by puromycin (1.5 μg...

Embodiment 2

[0040] To detect the presence of lncRNAs that may affect the sensitivity of Enz:

[0041] Based on the LNCipedia database, four lncRNAs, lnc-AR-1, lnc-AR-2, lnc-OPHN1-1 and lnc-OPHN1-5, were found, which were located at 1MB at the 5' end and 3' end of AR on the X chromosome ( figure 2 A), this experiment knocked out shRNA of four corresponding lncRNAs to test whether there are lncRNAs that may affect Enz sensitivity. The results showed that lnc-OPHN1-5 silencing could significantly reduce the Enz sensitivity of EnzS1-C4-2 cells ( figure 2 B-C, image 3 A-B), in contrast, increasing the expression of lnc-OPHN1-5 can significantly increase the Enz sensitivity of EnzR1-C4-2 cells ( figure 2 D-E). Similar results were obtained in EnzS2 / R2-C4-2B cells (Figure 2F-I). In addition, double confirmation of MTT data was performed using BrDU staining, and the results were consistent ( Figure 4 ).

[0042] Based on the analysis of the potential protein coding ability of lnc-OPHN1-...

Embodiment 3

[0044] Lnc-OPHN1-5 can alter AR protein expression and detection of transcriptional activity:

[0045] Since AR and AR signaling itself have a great influence on Enz sensitivity, and lnc-OPHN1-5 is located close to AR on the X chromosome, this experiment explored whether lnc-OPHN1-5 could regulate Enz sensitivity by changing AR expression or activity .

[0046] Consistent with previous findings that AR expression can directly affect Enz sensitivity (Fig. 5A), this study found that knocking out lnc-OPHN1-5 increased AR protein expression ( Figure 5 B), but failed to improve protein stability ( Figure 5 C-D), while ectopic lnc-OPHN1-5 expression inhibited AR protein expression ( Figure 5 B). Furthermore, knockdown of lnc-OPHN1-5 enhanced AR transactivation and increase of lnc-OPHN1-5 inhibited AR transactivation by MMTV-ARE-luciferase assay ( Figure 5 E-F). At the molecular level, qRT-PCR assays indicated that lnc-OPHN1-5 did not affect AR mRNA levels ( Figure 5 G-H)....

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Abstract

The invention provides lncRNA related to enzalutamide treatment sensitivity and application of the lncRNA to prostate cancer treatment by enzalutamide, and relates to the field of biological gene technologies. The lncRNA related to the enzalutamide treatment sensitivity is lnc-OPHN1-5, and the lnc-OPHN1-5 can increase the sensitivity of prostate cancer (PCa) to the enzalutamide (Enz) by reducing the translation of ARmRNA and the synthesis of AR protein. The lncRNA related to the enzalutamide treatment sensitivity overcomes the disadvantages of the prior art, and provides a new medical idea andstrategy for the treatment of castrated resistant prostate cancer (CRPC) and through the application of the lnc-OPHN1-5 in the prostate cancer treatment by the enzalutamide to improve the survival cycle of patients.

Description

technical field [0001] The invention relates to the technical field of biological genes, in particular to an lncRNA related to enzalutamide treatment sensitivity and its application in enzalutamide treatment of prostate cancer. Background technique [0002] Prostate cancer (PCa) is the most common cancer among men in Western countries. Although the recently developed androgen-deprivation therapy (ADT) with enzalutamide can prolong patient survival by 4.8 months 2-4 , most patients still develop resistance to ADT. An important molecular mechanism of ADT resistance is the continuous activation of AR protein, and the study of this new biological mechanism of abnormal activation of AR will help to improve the treatment of castration-resistant PCa (CRPC) patients. [0003] Studies have shown that during the development of CRPC, AR gene mutations, genome amplification and gene deletion are common, which eventually lead to the continuous activation and enhanced activity of AR. Re...

Claims

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Application Information

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IPC IPC(8): A61K31/4166A61K31/7105A61K48/00A61P35/00
CPCA61K31/4166A61K31/7105A61P35/00A61K2300/00
Inventor 张蒙孟佳林葛雅婷孙寅黄超娟郝宗耀张传祥梁朝朝
Owner THE FIRST AFFILIATED HOSPITAL OF ANHUI MEDICAL UNIV
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