PMID- 38021073
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231201
IS  - 2212-1366 (Print)
IS  - 2212-1374 (Electronic)
IS  - 2212-1366 (Linking)
VI  - 43
DP  - 2023 Dec
TI  - Long non-coding RNA PVT1 (PVT1) affects the expression of CCND1 and promotes 
      doxorubicin resistance in osteosarcoma cells.
PG  - 100512
LID - 10.1016/j.jbo.2023.100512 [doi]
LID - 100512
AB  - BACKGROUND: Acquired drug-resistance is the major risk factor for poor prognosis 
      and short-term survival in patients with osteosarcoma (OS). Accumulating evidence 
      has revealed that long noncoding RNAs (lncRNAs), including plasmacytoma variant 
      translocation 1 (PVT1), play potential regulatory roles in the malignant 
      development of OS. Considering the subcellular distribution of PVT1 as both 
      nuclear and cytoplasmic lncRNA, a thorough exploration of its extensive 
      mechanisms becomes essential. METHODS: The GEO database was utilized for the 
      acquisition of gene expression data, which was subsequently analyzed to fulfill 
      the research objectives. The subcellular localization of PVT1 in OS cells was 
      determined using fluorescence in situ hybridization (FISH) and quantitative 
      real-time polymerase chain reaction (qRT-PCR). Additionally, the sensitivity of 
      OS cells to doxorubicin was comprehensively evaluated through measurements of 
      cell viability, site-specific proliferation capacity, and the relative expression 
      abundance of multidrug resistance-related proteins (MRPs). In order to 
      investigate the differential response of OS cells with varying levels of PVT1 
      expression to doxorubicin, pulmonary metastasis mice models were established for 
      in vivo studies. Molecular interactions were further examined using the 
      dual-luciferase assay and RNA immunoprecipitation assay (RIP) to analyze the 
      binding sites of miR-15a-5p and miR-15b-5p on PVT1 and G1/S-specific cyclinD1 
      (CCND1) mRNA. Furthermore, the chromatin immunoprecipitation (ChIP) and 
      dual-luciferase assay were employed to assess the transcriptional activation of 
      the proto-oncogene c-myc (MYC) on the CCND1 promoter and identify the 
      corresponding binding sites. RESULTS: In doxorubicin resistant OS cells, 
      transcription levels of PVT1, MYC and CCND1 were significantly higher than those 
      in original cells. In vivo experiments demonstrated that OS cells rich in PVT1 
      expression exhibited enhanced tumorigenicity and resistance to doxorubicin. In 
      vitro experiments, it has been observed that overexpression of PVT1 in OS cells 
      is accompanied by an upregulation of CCND1, thereby facilitating resistance to 
      doxorubicin. Nonetheless, this PVT1-induced resistance can be effectively 
      attenuated by the knockdown of CCND1. Mechanistically, PVT1 functions as a 
      competitive endogenous RNA (ceRNA) that influences the expression of CCND1 by 
      inhibiting the degradation function of miR-15a-5p and miR-15b-5p on CCND1 mRNA. 
      Additionally, as a neighboring gene of MYC, PVT1 plays a role in maintaining MYC 
      protein stability, which further enhances MYC-dependent CCND1 transcriptional 
      activity. CONCLUSION: The resistance of OS cells to doxorubicin is facilitated by 
      PVT1, which enhances the expression of CCND1 through a dual mechanism. This 
      findings offer a novel perspective for comprehending the intricate regulatory 
      mechanisms of long non-coding RNA in influencing the expression of coding genes.
CI  - (c) 2023 The Authors.
FAU - Li, Zi
AU  - Li Z
AD  - Department of Orthopedics, The Second Xiangya Hospital, Central South University, 
      Changsha, Hunan, China.
FAU - Tian, Jia-Ming
AU  - Tian JM
AD  - Department of Orthopedics, The Second Xiangya Hospital, Central South University, 
      Changsha, Hunan, China.
FAU - Chu, Yi
AU  - Chu Y
AD  - Department of Gastroenterology, The Second Xiangya Hospital, Central South 
      University, Changsha, Hunan, China.
FAU - Zhu, Hong-Yi
AU  - Zhu HY
AD  - Department of Gastroenterology, The Second Xiangya Hospital, Central South 
      University, Changsha, Hunan, China.
FAU - Wang, Jun-Jie
AU  - Wang JJ
AD  - Department of Orthopedics, The Second Xiangya Hospital, Central South University, 
      Changsha, Hunan, China.
FAU - Huang, Jun
AU  - Huang J
AD  - Department of Orthopedics, The Second Xiangya Hospital, Central South University, 
      Changsha, Hunan, China.
LA  - eng
PT  - Journal Article
DEP - 20231107
PL  - Netherlands
TA  - J Bone Oncol
JT  - Journal of bone oncology
JID - 101610292
PMC - PMC10665705
OTO - NOTNLM
OT  - Acquired drug-resistance
OT  - CCND1
OT  - MYC
OT  - Osteosarcoma
OT  - PVT1
COIS- The authors declare that they have no known competing financial interests or 
      personal relationships that could have appeared to influence the work reported in 
      this paper.
EDAT- 2023/11/29 18:43
MHDA- 2023/11/29 18:44
PMCR- 2023/11/07
CRDT- 2023/11/29 14:57
PHST- 2023/08/04 00:00 [received]
PHST- 2023/11/01 00:00 [revised]
PHST- 2023/11/06 00:00 [accepted]
PHST- 2023/11/29 18:44 [medline]
PHST- 2023/11/29 18:43 [pubmed]
PHST- 2023/11/29 14:57 [entrez]
PHST- 2023/11/07 00:00 [pmc-release]
AID - S2212-1374(23)00045-3 [pii]
AID - 100512 [pii]
AID - 10.1016/j.jbo.2023.100512 [doi]
PST - epublish
SO  - J Bone Oncol. 2023 Nov 7;43:100512. doi: 10.1016/j.jbo.2023.100512. eCollection 
      2023 Dec.