Upregulated lncRNA PRNT promotes progression and oxaliplatin resistance of colorectal cancer cells by regulating HIPK2 transcription

Sai-Nan Li; Shan Yang; Hao-Qi Wang; Tian-Li Hui; Meng Cheng; Xi Zhang; Bao-Kun Li; Gui-Ying Wang

doi:10.4251/wjgo.v16.i4.1564

Upregulated lncRNA PRNT promotes progression and oxaliplatin resistance of colorectal cancer cells by regulating HIPK2 transcription

World J Gastrointest Oncol. 2024 Apr 15;16(4):1564-1577. doi: 10.4251/wjgo.v16.i4.1564.

Authors

Sai-Nan Li^{1

2}, Shan Yang¹, Hao-Qi Wang¹, Tian-Li Hui¹, Meng Cheng¹, Xi Zhang¹, Bao-Kun Li², Gui-Ying Wang^{2

3}

Affiliations

¹ The First Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China.
² The Second Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China.
³ Department of General Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China. hebeiwangguiying@163.com.

Abstract

Background: Colorectal cancer (CRC) is the third most common cancer and a significant cause of cancer-related mortality globally. Resistance to chemotherapy, especially during CRC treatment, leads to reduced effectiveness of drugs and poor patient outcomes. Long noncoding RNAs (lncRNAs) have been implicated in various pathophysiological processes of tumor cells, including chemotherapy resistance, yet the roles of many lncRNAs in CRC remain unclear.

Aim: To identify and analyze the lncRNAs involved in oxaliplatin resistance in CRC and to understand the underlying molecular mechanisms influencing this resistance.

Methods: Gene Expression Omnibus datasets GSE42387 and GSE30011 were reanalyzed to identify lncRNAs and mRNAs associated with oxaliplatin resistance. Various bioinformatics tools were employed to elucidate molecular mechanisms. The expression levels of lncRNAs and mRNAs were assessed via quantitative reverse transcription-polymerase chain reaction. Functional assays, including MTT, wound healing, and Transwell, were conducted to investigate the functional implications of lncRNA alterations. Interactions between lncRNAs and transcription factors were examined using RIP and luciferase reporter assays, while Western blotting was used to confirm downstream pathways. Additionally, a xenograft mouse model was utilized to study the in vivo effects of lncRNAs on chemotherapy resistance.

Results: LncRNA prion protein testis specific (PRNT) was found to be upregulated in oxaliplatin-resistant CRC cell lines and negatively correlated with homeodomain interacting protein kinase 2 (HIPK2) expression. PRNT was demonstrated to sponge transcription factor zinc finger protein 184 (ZNF184), which in turn could regulate HIPK2 expression. Altered expression of PRNT influenced CRC cell sensitivity to oxaliplatin, with overexpression leading to decreased sensitivity and decreased expression reducing resistance. Both RIP and luciferase reporter assays indicated that ZNF184 and HIPK2 are targets of PRNT. The PRNT/ZNF184/HIPK2 axis was implicated in promoting CRC progression and oxaliplatin resistance both in vitro and in vivo.

Conclusion: The study concludes that PRNT is upregulated in oxaliplatin-resistant CRC cells and modulates the expression of HIPK2 by sponging ZNF184. This regulatory mechanism enhances CRC progression and resistance to oxaliplatin, positioning PRNT as a promising therapeutic target for CRC patients undergoing oxaliplatin-based chemotherapy.

Keywords: Colorectal cancer; Homeodomain interacting protein kinase 2; Oxaliplatin resistance; Prion protein testis specific; Zinc finger protein 184.