Background: Current therapeutic outcomes for advanced colorectal cancer (CRC) remain suboptimal, and chemotherapy-based regimens continue to be the mainstay of treatment. Circular RNAs (circRNAs) can serve as templates for translating short peptides or proteins, and the resulting products actively regulate malignant tumour progression, making them attractive therapeutic targets.
Methods: We identified the novel protein PVT1-104aa translated from circPVT1, which is generated by back-splicing of the non-coding PVT1 gene. Its expression and clinical significance were examined in CRC clinical specimens and cell lines. Proliferation, metastasis, and tumour growth were assessed by CCK-8, colony formation, transwell, wound healing, and xenograft syngeneic tumour models. Mechanistic studies were performed by immunoprecipitation, ubiquitination assays, and protein half-life analysis. The relationship between PVT1-104aa, c-Myc, and PD-L1 was evaluated by promoter reporter assays, ChIP-qPCR, and immunohistochemistry. The therapeutic efficacy of combining PVT1-104aa inhibition with anti-PD-L1 therapy was tested in vivo.
Results: PVT1-104aa was significantly overexpressed in CRC and correlated with poor patient prognosis. Functionally, it drove tumour progression by promoting proliferation and metastasis. Mechanistically, PVT1-104aa enhanced c-Myc phosphorylation at Ser62, disrupted the c-Myc-FBW7 interaction, and thereby inhibited ubiquitin-mediated degradation of c-Myc, as shown by accelerated c-Myc turnover upon PVT1-104aa knockdown. In addition, PVT1-104aa regulated PD-L1 expression through c-Myc. Combining anti-PVT1-104aa with anti-PD-L1 therapy suppressed CRC growth and increased CD4+ and CD8+ T cell infiltration in xenograft syngeneic tumour models and CRC tissues.
Conclusions: Our results uncover a pathogenic role of the PVT1-originated molecular species PVT1-104aa and suggest that targeting this pathway represents a promising therapeutic strategy for CRC treatment.
Key points:
| [1] |
Biller LH, Schrag D. Diagnosis and treatment of metastatic colorectal cancer: a review. JAMA. 2021; 325: 669-685.
|
| [2] |
Tan L, Peng D, Cheng Y. Significant position of C-myc in colorectal cancer: a promising therapeutic target. Clin Transl Oncol. 2022; 24: 2295-2304.
|
| [3] |
Ye WL, Huang L, Yang XQ, et al. TRIM21 induces selective autophagic degradation of c-Myc and sensitizes regorafenib therapy in colorectal cancer. Proc Natl Acad Sci USA. 2024; 121:e2406936121.
|
| [4] |
Ghoussaini M, Song H, Koessler T, et al. Multiple loci with different cancer specificities within the 8q24 gene desert. J Natl Cancer Inst. 2008; 100: 962-966.
|
| [5] |
Sotelo J, Esposito D, Duhagon MA, et al. Long-range enhancers on 8q24 regulate c-Myc. Proc Natl Acad Sci USA. 2010; 107: 3001-3005.
|
| [6] |
Guan Y, Kuo WL, Stilwell JL, et al. Amplification of PVT1 contributes to the pathophysiology of ovarian and breast cancer. Clin Cancer Res. 2007; 13: 5745-5755.
|
| [7] |
Ghesquières H, Larrabee BR, Casasnovas O, et al. A susceptibility locus for classical Hodgkin lymphoma at 8q24 near MYC/PVT1 predicts patient outcome in two independent cohorts. Br J Haematol. 2018; 180: 286-290.
|
| [8] |
Riquelme E, Suraokar MB, Rodriguez J, et al. Frequent coamplification and cooperation between C-MYC and PVT1 oncogenes promote malignant pleural mesothelioma. J Thorac Oncol. 2014; 9: 998-1007.
|
| [9] |
Tseng YY, Moriarity BS, Gong W, et al. PVT1 dependence in cancer with MYC copy-number increase. Nature. 2014; 512: 82-86.
|
| [10] |
Fei Y, Cao D, Li Y, et al. Circ_0008315 promotes tumorigenesis and cisplatin resistance and acts as a nanotherapeutic target in gastric cancer. J Nanobiotechnol. 2024; 22: 519.
|
| [11] |
Li Y, Wang Z, Gao P, et al. CircRHBDD1 promotes immune escape via IGF2BP2/PD-L1 signaling and acts as a nanotherapeutic target in gastric cancer. J Transl Med. 2024; 22: 704.
|
| [12] |
Hansen TB, Jensen TI, Clausen BH, et al. Natural RNA circles function as efficient microRNA sponges. Nature. 2013; 495: 384-388.
|
| [13] |
Pamudurti NR, Bartok O, Jens M, et al. Translation of CircRNAs. Mol Cell. 2017; 66: 9-21.e7.
|
| [14] |
Zhong J, Yang X, Chen J, et al. Circular EZH2-encoded EZH2-92aa mediates immune evasion in glioblastoma via inhibition of surface NKG2D ligands. Nat Commun. 2022; 13: 4795.
|
| [15] |
Panda AC, Grammatikakis I, Kim KM, et al. Identification of senescence-associated circular RNAs (SAC-RNAs) reveals senescence suppressor CircPVT1. Nucleic Acids Res. 2017; 45: 4021-4035.
|
| [16] |
Yi J, Wang L, Hu GS, et al. CircPVT1 promotes ER-positive breast tumorigenesis and drug resistance by targeting ESR1 and MAVS. Embo J. 2023; 42:e112408.
|
| [17] |
Wang S, Su TT, Tong H, et al. CircPVT1 promotes gallbladder cancer growth by sponging miR-339-3p and regulates MCL-1 expression. Cell Death Discov. 2021; 7: 191.
|
| [18] |
Welcker M, Orian A, Jin J, et al. The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proc Natl Acad Sci USA. 2004; 101: 9085-9090.
|
| [19] |
Rottmann S, Wang Y, Nasoff M, Deveraux QL, Quon KC. A TRAIL receptor-dependent synthetic lethal relationship between MYC activation and GSK3beta/FBW7 loss of function. Proc Natl Acad Sci USA. 2005; 102: 15195-15200.
|
| [20] |
Casey SC, Tong L, Li Y, et al. MYC regulates the antitumor immune response through CD47 and PD-L1. Science. 2016; 352: 227-231.
|
| [21] |
Kim EY, Kim A, Kim SK, Y S. Chang MYC expression correlates with PD-L1 expression in non-small cell lung cancer. Lung Cancer. 2017; 110: 63-67.
|
| [22] |
Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015; 372: 2509-2520.
|
| [23] |
Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018; 36: 773-779.
|
| [24] |
Vo JN, Cieslik M, Zhang Y, et al. The landscape of circular RNA in cancer. Cell. 2019; 176: 869-881.e13.
|
| [25] |
Yang Y, Gao X, Zhang M, et al. Novel role of FBXW7 circular RNA in repressing glioma tumorigenesis. J Natl Cancer Inst. 2018; 110: 304-315.
|
| [26] |
Zhong J, Wu X, Gao Y, et al. Circular RNA encoded MET variant promotes glioblastoma tumorigenesis. Nat Commun. 2023; 14: 4467.
|
| [27] |
Li J, Ma M, Yang X, et al. Circular HER2 RNA positive triple negative breast cancer is sensitive to Pertuzumab. Mol Cancer. 2020; 19: 142.
|
| [28] |
Dhanasekaran R, Deutzmann A, Mahauad-Fernandez WD, et al. The MYC oncogene—the grand orchestrator of cancer growth and immune evasion. Nat Rev Clin Oncol. 2022; 19: 23-36.
|
| [29] |
D'Artista L, Moschopoulou AA, Barozzi I, et al. MYC determines lineage commitment in KRAS-driven primary liver cancer development. J Hepatol. 2023; 79: 141-149.
|
| [30] |
Zimmerli D, Brambillasca CS, Talens F, et al. MYC promotes immune-suppression in triple-negative breast cancer via inhibition of interferon signaling. Nat Commun. 2022; 13: 6579.
|
| [31] |
Klein IA, Resch W, Jankovic M, et al. Translocation-capture sequencing reveals the extent and nature of chromosomal rearrangements in B lymphocytes. Cell. 2011; 147: 95-106.
|
| [32] |
Llombart V, Mansour MR. Therapeutic targeting of “undruggable” MYC. EBioMedicine. 2022; 75:103756.
|
| [33] |
Yan S, Zhang G, Luo W, et al. PROTAC technology: from drug development to probe technology for target deconvolution. Eur J Med Chem. 2024; 276:116725.
|
| [34] |
Qin S, Xiao X. Key advances and application prospects of PROTAC technologies in the next 5 years. Future Med Chem. 2025; 17: 987-989.
|
| [35] |
Han H, Jain AD, Truica MI, et al. Small-molecule MYC inhibitors suppress tumor growth and enhance immunotherapy. Cancer Cell. 2019; 36: 483-497.e15.
|
| [36] |
Yin Y, Liu B, Cao Y, et al. Colorectal cancer-derived small extracellular vesicles promote tumor immune evasion by upregulating PD-L1 expression in tumor-associated macrophages. Adv Sci (Weinh). 2022; 9:2102620.
|
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2026 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
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