LncRNA RP3-326I13.1 promotes cisplatin resistance in lung adenocarcinoma by binding to HSP90B and upregulating MMP13

Cell Cycle. 2022 Jul;21(13):1391-1405. doi: 10.1080/15384101.2022.2051971. Epub 2022 Mar 17.

Abstract

Cisplatin (DDP) resistance has become the major obstacle in the therapy of malignant tumors, including lung adenocarcinoma (LAD). Long non-coding RNAs (lncRNAs) were confirmed to be related to DDP-resistance. Studies have shown that RP3-326I13.1 (also known as PINCR) could promote the progression of colorectal cancer, and RP3-326I13.1 knockdown could induce hypersensitivity to chemotherapy drugs. While the function of RP3-326I13.1 in LAD is unclear, therefore, this study aimed to research the biological function and related molecular mechanisms of RP3-326I13.1 in DDP-resistance of LAD. QPCR analysis found that RP3-326I13.1 was highly expressed in A549/DDP cells and LAD tissues. Cytological assays found that RP3-326I13.1 pro-moted the proliferation, migration, invasion, and DDP-resistance of LAD cell lines. Moreover, knock-down of RP3-326I13.1 could induce G1 phase arrest. Nude mouse xenograft assay confirmed that RP3-326I13.1 could promote tumor growth and DDP-resistance in vivo. Mechanically, RNA pull-down and mass spectrometry analysis indicated that heat shock protein HSP 90-beta (HSP90B) could be combined with RP3-326I13.1. HSP90B knockdown inhibited the effect of RP3-326I13.1 on proliferation, invasion, and promoted LAD cell lines apoptosis. Transcriptome sequencing analysis found that MMP13 was the downstream mRNA of RP3-326I13.1. In conclusion, RP3-326I13.1 could promote DDP-resistance of LAD by binding to HSP90B and upregulating human matrix metalloproteinase-13 (MMP-13) and may serve as a therapeutic target, as well as a biomarker for predicting DDP-resistance in LAD.Abbreviations:DDP: Cisplatin; LAD: Lung adenocarcinoma; LncRNAs: Long non-coding RNAs; qPCR: real-time fluorescent quantitative PCR; HSP90B: Heat shock protein HSP 90-beta; RPMI: Roswell Park Memorial Institute; FBS: Fetal bovine serum; CT: computed tomography; MRI: magnetic resonance imaging; RECIST: Response evaluation criteria in solid tumors; NC: Negative control; OE: overexpression; shRNA: short hairpin RNA; siRNA: small interfering RNA; CCK-8: Cell Counting Kit-8; IC50: The half maximal inhibitory concentration; PBS: Phosphate buffer saline; PI: propidium iodide; SDS-PAGE: sodiumdodecylsulfate-polyacrylamide gel electrophoresis; ceRNA: Competing endogenous RNA; HE: hematoxylin-eosin; ns: no significance.

Keywords: Lung adenocarcinoma; RP3-326I13.1; cisplatin resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma* / pathology
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Cisplatin / therapeutic use
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Neoplastic
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Lung / metabolism
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / pathology
  • Matrix Metalloproteinase 13 / genetics
  • Matrix Metalloproteinase 13 / metabolism
  • Matrix Metalloproteinase 13 / pharmacology
  • Membrane Glycoproteins
  • Mice
  • RNA, Long Noncoding* / genetics
  • RNA, Long Noncoding* / metabolism
  • RNA, Small Interfering / metabolism

Substances

  • HSP90 Heat-Shock Proteins
  • Membrane Glycoproteins
  • RNA, Long Noncoding
  • RNA, Small Interfering
  • endoplasmin
  • MMP13 protein, human
  • Matrix Metalloproteinase 13
  • Cisplatin

Grants and funding

This work was supported by Zhejiang Provincial Natural Science Foundation [grant no. LY19H200002], the National Natural Science Foundation of China [grant no. 81672088], the Wenzhou Municipal Science and Technology Bureau of China [grant no. Y20190461] and Zhejiang Provincial Research Center for Cancer Intelligent Diagnosis and Molecular Technology [grant no. JBZX-202003].