ABSTRACT Multiple transcript isoforms of genes can be formed by processing and modifying the 5′ and 3′ ends of RNA. Herein, the aim of this study is to uncover the characteristics of RNA

processing modification (RPM) in hepatocellular carcinoma (HCC), and to identify novel biomarkers and potential targets for treatment. Firstly, integrated bioinformatics analysis was carried

out to identify risk prognostic RPM regulators (RPMRs). Then, we used these RPMRs to identify subtypes of HCC and explore differences in immune microenvironment and cellular function

improvement pathways between the sub-types. Finally, we used the principal component analysis algorithms to estimate RPMscore, which were applied to 5 cohorts. Lower RPMscore among patients

Preclinically, patients with high RPMscore might benefit from immunotherapy. The RPMscore is helpful in clustering HCC patients with distinct prognosis and immunotherapy. Our RPMscore model

can help clinicians to select personalized therapy for HCC patients, and RPMscore may act a part in the development of HCC. Access through your institution Buy or subscribe This is a preview

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PROFILING REVEALS PBMC RNA AS A POTENTIAL BIOMARKER FOR HEPATOCELLULAR CARCINOMA Article Open access 07 September 2021 TMEM101 EXPRESSION AND ITS IMPACT ON IMMUNE CELL INFILTRATION AND

PROGNOSIS IN HEPATOCELLULAR CARCINOMA Article Open access 30 December 2024 A-TO-I RNA CO-EDITING PREDICTS CLINICAL OUTCOMES AND IS ASSOCIATED WITH IMMUNE CELLS INFILTRATION IN HEPATOCELLULAR

CARCINOMA Article Open access 09 July 2024 DATA AVAILABILITY The datasets generated for this study can be found in the GEO database (GSE14520, GSE36376, GSE76427, GSE20140, GSE27150,

GSE140901; https://www.ncbi.nlm.nih.gov/geo/), and UCSC Xena website (https://gdc.xenahubs.net). REFERENCES * Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA: a cancer J

Clin. 2023;73:17–48. Google Scholar  * Vogel A, Meyer T, Sapisochin G, Salem R, Saborowski A. Hepatocellular carcinoma. Lancet (Lond, Engl). 2022;400:1345–62. Article  CAS  Google Scholar 

* Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol.

2019;16:589–604. Article  PubMed  PubMed Central  Google Scholar  * Sangro B, Sarobe P, Hervás-Stubbs S, Melero I. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev

Gastroenterol Hepatol. 2021;18:525–43. Article  PubMed  PubMed Central  Google Scholar  * Llovet JM, Castet F, Heikenwalder M, Maini MK, Mazzaferro V, Pinato DJ, et al. Immunotherapies for

hepatocellular carcinoma. Nat Rev Clin Oncol. 2022;19:151–72. Article  CAS  PubMed  Google Scholar  * Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, et al. Pembrolizumab in

patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19:940–52. Article  PubMed 

Google Scholar  * Gok Yavuz B, Hasanov E, Lee SS, Mohamed YI, Curran MA, Koay EJ, et al. Current Landscape and Future Directions of Biomarkers for Immunotherapy in Hepatocellular Carcinoma.

J Hepatocell carcinoma. 2021;8:1195–207. Article  PubMed  PubMed Central  Google Scholar  * Ayuso C, Rimola J, Vilana R, Burrel M, Darnell A, García-Criado Á, et al. Diagnosis and staging of

hepatocellular carcinoma (HCC): current guidelines. Eur J Radiol. 2018;101:72–81. Article  PubMed  Google Scholar  * Reyes A, Huber W. Alternative start and termination sites of

transcription drive most transcript isoform differences across human tissues. Nucleic acids Res. 2018;46:582–92. Article  CAS  PubMed  Google Scholar  * Gruber AJ, Zavolan M. Alternative

cleavage and polyadenylation in health and disease. Nat Rev Genet. 2019;20:599–614. Article  CAS  PubMed  Google Scholar  * Tan S, Zhang M, Shi X, Ding K, Zhao Q, Guo Q, et al. CPSF6 links

alternative polyadenylation to metabolism adaption in hepatocellular carcinoma progression. J Exp Clin Cancer Res: CR. 2021;40:85. Article  CAS  PubMed  PubMed Central  Google Scholar  *

Chen SL, Zhu ZX, Yang X, Liu LL, He YF, Yang MM, et al. Cleavage and Polyadenylation Specific Factor 1 Promotes Tumor Progression via Alternative Polyadenylation and Splicing in

Hepatocellular Carcinoma. Front cell Dev Biol. 2021;9:616835. Article  PubMed  PubMed Central  Google Scholar  * Zeng X, Liao G, Li S, Liu H, Zhao X, Li S, et al. Eliminating METTL1-mediated

accumulation of PMN-MDSCs prevents hepatocellular carcinoma recurrence after radiofrequency ablation. Hepatol (Baltim, Md). 2023;77:1122–38. Article  Google Scholar  * Zhao S, Ye Z, Stanton

R. Misuse of RPKM or TPM normalization when comparing across samples and sequencing protocols. RNA (N.Y, N.Y). 2020;26:903–9. Article  CAS  Google Scholar  * Parker HS, Leek JT, Favorov AV,

Considine M, Xia X, Chavan S, et al. Preserving biological heterogeneity with a permuted surrogate variable analysis for genomics batch correction. Bioinforma (Oxf, Engl). 2014;30:2757–63.

CAS  Google Scholar  * Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.

Nature. 2018;554:544–8. Article  CAS  PubMed  PubMed Central  Google Scholar  * Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. Limma powers differential expression analyses for

RNA-sequencing and microarray studies. Nucleic acids Res. 2015;43:e47. Article  PubMed  PubMed Central  Google Scholar  * Wilkerson MD, Hayes DN. ConsensusClusterPlus: a class discovery tool

with confidence assessments and item tracking. Bioinforma (Oxf, Engl). 2010;26:1572–3. CAS  Google Scholar  * Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z, et al. clusterProfiler 4.0: A universal

enrichment tool for interpreting omics data. Innov (Camb (Mass)). 2021;2:100141. CAS  Google Scholar  * Yoshihara K, Shahmoradgoli M, Martínez E, Vegesna R, Kim H, Torres-Garcia W, et al.

Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013;4:2612. Article  PubMed  Google Scholar  * Finotello F, Trajanoski Z. Quantifying

tumor-infiltrating immune cells from transcriptomics data. Cancer Immunol, Immunother: CII. 2018;67:1031–40. Article  CAS  PubMed  Google Scholar  * Newman AM, Liu CL, Green MR, Gentles AJ,

Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat methods. 2015;12:453–7. Article  CAS  PubMed  PubMed Central  Google Scholar  * Aran D, Hu Z,

Butte AJ. xCell: digitally portraying the tissue cellular heterogeneity landscape. Genome Biol. 2017;18:220. Article  PubMed  PubMed Central  Google Scholar  * Subramanian A, Tamayo P,

Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA.

2005;102:15545–50. Article  CAS  PubMed  PubMed Central  Google Scholar  * Su Y, Huang J, Hu J. m(6)A RNA Methylation Regulators Contribute to Malignant Progression and Have Clinical

Prognostic Impact in Gastric Cancer. Front Oncol. 2019;9:1038. Article  PubMed  PubMed Central  Google Scholar  * Wang X, Zhang S, Han K, Wang L, Liu X. Induction of Apoptosis by Matrine

Derivative ZS17 in Human Hepatocellular Carcinoma BEL-7402 and HepG2 Cells through ROS-JNK-P53 Signalling Pathway Activation. Int J Mol Sci. 2022;23:15991. Article  CAS  PubMed  PubMed

Central  Google Scholar  * Li XY, Cui X, Xie CQ, Wu Y, Song T, He JD, et al. Andrographolide causes p53-independent HCC cell death through p62 accumulation and impaired DNA damage repair.

Phytomed: Int J Phytother phytopharmacol. 2023;121:155089. Article  CAS  Google Scholar  * Tang B, Zhu J, Wang Y, Chen W, Fang S, Mao W, et al. Targeted xCT-mediated Ferroptosis and

Protumoral Polarization of Macrophages Is Effective against HCC and Enhances the Efficacy of the Anti-PD-1/L1 Response. Adv Sci (Weinh, Baden-Wurtt, Ger). 2023;10:e2203973. Google Scholar  *

Chen Q, Zheng W, Guan J, Liu H, Dan Y, Zhu L, et al. SOCS2-enhanced ubiquitination of SLC7A11 promotes ferroptosis and radiosensitization in hepatocellular carcinoma. Cell Death Differ.

2023;30:137–51. Article  CAS  PubMed  Google Scholar  * Jiang N, Yu Y, Wu D, Wang S, Fang Y, Miao H, et al. HLA and tumour immunology: immune escape, immunotherapy and immune-related adverse

events. J Cancer Res Clin Oncol. 2023;149:737–47. Article  PubMed  Google Scholar  * Zhan X, Wu R, Kong XH, You Y, He K, Sun XY, et al. Elevated neutrophil extracellular traps by

HBV-mediated S100A9-TLR4/RAGE-ROS cascade facilitate the growth and metastasis of hepatocellular carcinoma. Cancer Commun (Lond, Engl). 2023;43:225–45. Article  Google Scholar  * Zhou C,

Weng J, Liu C, Liu S, Hu Z, Xie X, et al. Disruption of SLFN11 Deficiency-Induced CCL2 Signaling and Macrophage M2 Polarization Potentiates Anti-PD-1 Therapy Efficacy in Hepatocellular

Carcinoma. Gastroenterology. 2023;164:1261–78. Article  CAS  PubMed  Google Scholar  * Jiang Y, Hong K, Zhao Y, Xu K. Emerging role of deubiquitination modifications of programmed

death-ligand 1 in cancer immunotherapy. Front Immunol. 2023;14:1228200. Article  CAS  PubMed  PubMed Central  Google Scholar  * Yuan X, Zhou J, Zhou L, Huang Z, Wang W, Qiu J, et al.

Apoptosis-Related Gene-Mediated Cell Death Pattern Induces Immunosuppression and Immunotherapy Resistance in Gastric Cancer. Front Genet. 2022;13:921163. Article  CAS  PubMed  PubMed Central

  Google Scholar  * Ma P, Zou C, Xia S. Oncogenic signaling pathway mediated by Notch pathway-related genes induces immunosuppression and immunotherapy resistance in hepatocellular

carcinoma. Immunogenetics. 2022;74:539–57. Article  CAS  PubMed  Google Scholar  * Zhou L, Xu G, Huang F, Chen W, Zhang J, Tang Y. Apoptosis related genes mediated molecular subtypes depict

the hallmarks of the tumor microenvironment and guide immunotherapy in bladder cancer. BMC Med Genomics. 2023;16:88. Article  CAS  PubMed  PubMed Central  Google Scholar  * Wang S, Chen L,

Liu W. Matrix stiffness-dependent STEAP3 coordinated with PD-L2 identify tumor responding to sorafenib treatment in hepatocellular carcinoma. Cancer cell Int. 2022;22:318. Article  CAS 

PubMed  PubMed Central  Google Scholar  * Nie X, Chen W, Zhu Y, Huang B, Yu W, Wu Z, et al. B7-DC (PD-L2) costimulation of CD4(+) T-helper 1 response via RGMb. Cell Mol Immunol.

2018;15:888–97. Article  CAS  PubMed  Google Scholar  Download references FUNDING This research was supported by the Construction of Major Subject [Grant no. (YNZDXK202201, 2022-2025)] of

Huadu District People´s Hospital of Guangzhou; the construction project of inheritance studio of national famous and old traditional Chinese Medicine experts (Grant no.140000020132). AUTHOR

INFORMATION Author notes * These authors contributed equally: Xinhui Li, Shan Liu, Laibin Zou. AUTHORS AND AFFILIATIONS * Department of Oncology, Renmin Hospital, Hubei University of

Medicine, Shiyan, Hubei, 442000, PR China Xinhui Li & Shan Liu * Department of Hepatobiliary and Pancreatic Surgery, Huadu District People´s Hospital of Guangzhou, The Third School of

Clinical Medicine, Southern Medical University, Guangzhou, 510800, China Laibin Zou * Department of Traditional Chinese Medicine and Allergy, The third affiliated hospital of Sun Yet-sen

University, Guangzhou, 510800, China Min Dai * Department of Gastroenterology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, PR China Chaobei Zhu Authors * Xinhui Li

View author publications You can also search for this author inPubMed Google Scholar * Shan Liu View author publications You can also search for this author inPubMed Google Scholar * Laibin

Zou View author publications You can also search for this author inPubMed Google Scholar * Min Dai View author publications You can also search for this author inPubMed Google Scholar *

Chaobei Zhu View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS M.D. and X.H.L. conceived the project. S.L. acquired and processed raw

sequencing data. L.B.Z. performed data integration and conducted data analysis. X.H.L. and S.L. assisted in the interpretation of results. C.B.Z. wrote the manuscript. All authors read and

approved the final manuscript. CORRESPONDING AUTHORS Correspondence to Min Dai or Chaobei Zhu. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. ETHICAL

APPROVAL The study was approved by the ethical committee in the Renmin Hospital, Hubei University of Medicine, and conducted under the guidance of the Declaration of Helsinki. ADDITIONAL

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law. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Li, X., Liu, S., Zou, L. _et al._ RNA processing modification mediated subtypes illustrate the distinctive features of

tumor microenvironment in hepatocellular carcinoma. _Genes Immun_ 25, 132–148 (2024). https://doi.org/10.1038/s41435-024-00265-8 Download citation * Received: 16 December 2023 * Revised: 26

February 2024 * Accepted: 27 February 2024 * Published: 12 March 2024 * Issue Date: April 2024 * DOI: https://doi.org/10.1038/s41435-024-00265-8 SHARE THIS ARTICLE Anyone you share the

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