<em>RIPK3</em> modulates sarcoma through immune checkpoint <em>HAVCR2</em>

Qian,Chen; Qian,Chen; Qian,Chen; Qian,Chen; Qian,Chen; Qian,Chen; Wu,Deluo; Wu,Deluo; Wu,Deluo; Wu,Deluo; Wu,Deluo; Wu,Deluo; Du,Jianwei; Du,Jianwei; Du,Jianwei; Du,Jianwei; Du,Jianwei; Du,Jianwei

doi:10.3892/ol.2022.13501

RIPK3 modulates sarcoma through immune checkpoint HAVCR2

Authors:
- Chen Qian
- Deluo Wu
- Jianwei Du
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Affiliations: Department of Orthopedics, Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
Published online on: September 13, 2022 https://doi.org/10.3892/ol.2022.13501
Article Number: 381
Copyright: © Qian et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Sarcomas is a complex group of malignant diseasse with undetermined molecular mechanisms. Receptor interacting serine/threonine kinase 3 (RIPK3) is a necroptosis‑ and apoptosis‑related marker that has been implicated in several immune‑associated diseases and aggressive malignant tumours. In the present study, publicly available transcriptome sequencing data were collected from The Cancer Genome Atlas (TCGA) and Therapeutically Applicable Research To Generate Effective Treatments (TARGET) databases and extensive data mining was performed, focusing on RIPK3 and its potential function in the modulation of gene expression and signaling pathways, immune checkpoints and cell infiltration. Analysis of TCGA and TARGET data revealed 603 up‑ and 260 downregulated genes in the higher RIPK3 expression group compared with the lower RIPK3 expression groups, with transmembrane channel like 8 and transmembrane protein 97 as the top up‑ and downregulated genes, respectively. Further pathway analysis revealed that the overexpressed genes were enriched in ‘cytokine‑cytokine receptor interaction’. Higher RIPK3 was found to be associated with improved survival, the immune checkpoint gene hepatitis A virus cellular receptor 2 (HAVCR2) and an improved response to immune blockade therapy. The potential modulation of HAVCR2 expression by RIPK3 was confirmed by reverse transcription‑quantiative PCR in KHOS and 143B human osteosarcoma cell lines. Immune cell infiltration analysis revealed that RIPK3 was positively associated with macrophage and monocyte infiltration, suggesting that RIPK3 executes its function through these immune cells. These findings led to the hypothesis that increased RIPK3 expression may result in improved survival, possibly by regulating the immune checkpoint HAVCR2. In conclusion, the present study comprehensively elucidated the RIPK3 profile with regard to sarcoma survival, transcriptome expression, immune checkpoint therapy and immune cell infiltration. These findings suggest that RIPK3 is potentially a therapeutic target for sarcoma.

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1	Popovich JR, Kashyap S and Cassaro S: Sarcoma. In: StatPearls. Treasure Island (FL). 2022.
2	Bui NQ, Wang DS and Hiniker SM: Contemporary management of metastatic soft tissue sarcoma. Curr Probl Cancer. 43:289–299. 2019. View Article : Google Scholar : PubMed/NCBI
3	Howitt BE, Sholl LM, Dal Cin P, Jia Y, Yuan L, MacConaill L, Lindeman N, Kuo F, Garcia E, Nucci MR and Quade BJ: Targeted genomic analysis of mullerian adenosarcoma. J Pathol. 235:37–49. 2015. View Article : Google Scholar
4	Mirabello L, Zhu B, Koster R, Karlins E, Dean M, Yeager M, Gianferante M, Spector LG, Morton LM, Karyadi D, et al: Frequency of pathogenic germline variants in cancer-susceptibility genes in patients with osteosarcoma. JAMA Oncol. 6:724–734. 2020. View Article : Google Scholar
5	Koelsche C, Schrimpf D, Stichel D, Sill M, Sahm F, Reuss DE, Blattner M, Worst B, Heilig CE, Beck K, et al: Sarcoma classification by DNA methylation profiling. Nat Commun. 12:4982021. View Article : Google Scholar : PubMed/NCBI
6	Steele CD and Pillay N: The genomics of undifferentiated sarcoma of soft tissue: Progress, challenges and opportunities. Semin Cancer Biol. 61:42–55. 2020. View Article : Google Scholar
7	Cancer Genome Atlas Research Network, . Electronic address. simpleelizabeth.demicco@sinaihealthsystem.caCancer Genome Atlas Research Network: Comprehensive and integrated genomic characterization of adult soft tissue sarcomas. Cell. 171:950–965.e28. 2017. View Article : Google Scholar
8	Jensen S, Seidelin JB, LaCasse EC and Nielsen OH: SMAC mimetics and RIPK inhibitors as therapeutics for chronic inflammatory diseases. Sci Signal. 13:eaax82952020. View Article : Google Scholar
9	Duan X, Liu X, Liu N, Huang Y, Jin Z, Zhang S, Ming Z and Chen H: Inhibition of keratinocyte necroptosis mediated by RIPK1/RIPK3/MLKL provides a protective effect against psoriatic inflammation. Cell Death Dis. 11:1342020. View Article : Google Scholar : PubMed/NCBI
10	Otsubo K, Maeyashiki C, Nibe Y, Tamura A, Aonuma E, Matsuda H, Kobayashi M, Onizawa M, Nemoto Y, Nagaishi T, et al: Receptor-Interacting Protein Kinase 3 (RIPK3) inhibits autophagic flux during necroptosis in intestinal epithelial cells. FEBS Lett. 594:1586–1595. 2020. View Article : Google Scholar
11	Wu S, Xu C, Xia K, Lin Y, Tian S, Ma H, Ji Y, Zhu F, He S and Zhang X: Ring closure strategy leads to potent RIPK3 inhibitors. Eur J Med Chem. 217:1133272021. View Article : Google Scholar : PubMed/NCBI
12	Karlsson J, Holmquist Mengelbier L, Ciornei CD, Naranjo A, O'Sullivan MJ and Gisselsson D: Clear cell sarcoma of the kidney demonstrates an embryonic signature indicative of a primitive nephrogenic origin. Genes Chromosomes Cancer. 53:381–391. 2014. View Article : Google Scholar : PubMed/NCBI
13	Ravi R, Noonan KA, Pham V, Bedi R, Zhavoronkov A, Ozerov IV, Makarev E, Artemov A, Wysocki PT, Mehra R, et al: Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy. Nat Commun. 9:7412018. View Article : Google Scholar : PubMed/NCBI
14	Zeng D, Li M, Zhou R, Zhang J, Sun H, Shi M, Bin J, Liao Y, Rao J and Liao W: Tumor microenvironment characterization in gastric cancer identifies prognostic and immunotherapeutically relevant gene signatures. Cancer Immunol Res. 7:737–750. 2019. View Article : Google Scholar : PubMed/NCBI
15	Wang J, Sun J, Liu LN, Flies DB, Nie X, Toki M, Zhang J, Song C, Zarr M, Zhou X, et al: Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy. Nat Med. 25:656–666. 2019. View Article : Google Scholar : PubMed/NCBI
16	Tirosh I, Izar B, Prakadan SM, Wadsworth MH II, Treacy D, Trombetta JJ, Rotem A, Rodman C, Lian C, Murphy G, et al: Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science. 352:189–196. 2016. View Article : Google Scholar : PubMed/NCBI
17	Lin B, Wang S, Yao Y, Shen Y and Yang H: Comprehensive co-expression analysis reveals TMC8 as a prognostic immune-associated gene in head and neck squamous cancer. Oncol Lett. 22:4982021. View Article : Google Scholar
18	Ding H, Gui XH, Lin XB, Chen RH, Cai HR, Fen Y and Sheng YL: Prognostic value of MAC30 expression in human pure squamous cell carcinomas of the lung. Asian Pac J Cancer Prev. 17:2705–2710. 2016.PubMed/NCBI
19	Mandal P, Berger SB, Pillay S, Moriwaki K, Huang C, Guo H, Lich JD, Finger J, Kasparcova V, Votta B, et al: RIP3 induces apoptosis independent of pronecrotic kinase activity. Mol Cell. 56:481–495. 2014. View Article : Google Scholar
20	André S, Picard M, Cezar R, Roux-Dalvai F, Alleaume-Butaux A, Soundaramourty C, Cruz AS, Mendes-Frias A, Gotti C, Leclercq M, et al: T cell apoptosis characterizes severe Covid-19 disease. Cell Death Differ. 29:1486–1499. 2022. View Article : Google Scholar
21	Chen X, Zhu R, Zhong J, Ying Y, Wang W, Cao Y, Cai H, Li X, Shuai J and Han J: Mosaic composition of RIP1-RIP3 signalling hub and its role in regulating cell death. Nat Cell Biol. 24:471–482. 2022. View Article : Google Scholar
22	Jiang P, Gu S, Pan D, Fu J, Sahu A, Hu X, Li Z, Traugh N, Bu X, Li B, et al: Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat Med. 24:1550–1558. 2018. View Article : Google Scholar : PubMed/NCBI
23	Racle J, de Jonge K, Baumgaertner P, Speiser DE and Gfeller D: Simultaneous enumeration of cancer and immune cell types from bulk tumor gene expression data. Elife. 6:e264762017. View Article : Google Scholar : PubMed/NCBI
24	Bieging KT, Mello SS and Attardi LD: Unravelling mechanisms of p53-mediated tumour suppression. Nat Rev Cancer. 14:359–370. 2014. View Article : Google Scholar : PubMed/NCBI
25	Liu Y, Sánchez-Tilló E, Lu X, Clem B, Telang S, Jenson AB, Cuatrecasas M, Chesney J, Postigo A and Dean DC: Rb1 family mutation is sufficient for sarcoma initiation. Nat Commun. 4:26502013. View Article : Google Scholar : PubMed/NCBI
26	Tian W, Li Y, Zhang J, Li J and Gao J: Combined analysis of DNA methylation and gene expression profiles of osteosarcoma identified several prognosis signatures. Gene. 650:7–14. 2018. View Article : Google Scholar : PubMed/NCBI
27	Coupienne I, Fettweis G and Piette J: RIP3 expression induces a death profile change in U2OS osteosarcoma cells after 5-ALA-PDT. Lasers Surg Med. 43:557–564. 2011. View Article : Google Scholar : PubMed/NCBI
28	Tuohy JL, Somarelli JA, Borst LB, Eward WC, Lascelles BD and Fogle JE: Immune dysregulation and osteosarcoma: Staphylococcus aureus downregulates TGF-β and heightens the inflammatory signature in human and canine macrophages suppressed by osteosarcoma. Vet Comp Oncol. 18:64–75. 2020. View Article : Google Scholar
29	Castro FA, Ivansson EL, Schmitt M, Juko-Pecirep I, Kjellberg L, Hildesheim A, Gyllensten UB and Pawlita M: Contribution of TMC6 and TMC8 (EVER1 and EVER2) variants to cervical cancer susceptibility. Int J Cancer. 130:349–355. 2012. View Article : Google Scholar : PubMed/NCBI
30	Ramalho-Carvalho J, Gonçalves CS, Graça I, Bidarra D, Pereira-Silva E, Salta S, Godinho MI, Gomez A, Esteller M, Costa BM, et al: A multiplatform approach identifies miR-152-3p as a common epigenetically regulated onco-suppressor in prostate cancer targeting TMEM97. Clin Epigenetics. 10:402018. View Article : Google Scholar : PubMed/NCBI
31	Ding H, Gui X, Lin X, Chen R, Ma T, Sheng Y, Cai H and Fen Y: The prognostic effect of MAC30 expression on patients with non-small cell lung cancer receiving adjuvant chemotherapy. Technol Cancer Res Treat. 16:645–653. 2017. View Article : Google Scholar
32	Xiao M, Li H, Yang S, Huang Y, Jia S, Wang H, Wang J and Li Z: Expression of MAC30 protein is related to survival and clinicopathological variables in breast cancer. J Surg Oncol. 107:456–462. 2013. View Article : Google Scholar
33	Workenhe ST, Nguyen A, Bakhshinyan D, Wei J, Hare DN, MacNeill KL, Wan Y, Oberst A, Bramson JL, Nasir JA, et al: De novo necroptosis creates an inflammatory environment mediating tumor susceptibility to immune checkpoint inhibitors. Commun Biol. 3:6452020. View Article : Google Scholar
34	Bagchi S, Yuan R and Engleman EG: Immune checkpoint inhibitors for the treatment of cancer: Clinical impact and mechanisms of response and resistance. Annu Rev Pathol. 16:223–249. 2021. View Article : Google Scholar
35	Gyrd-Hansen M and Meier P: IAPs: From caspase inhibitors to modulators of NF-kappaB, inflammation and cancer. Nat Rev Cancer. 10:561–574. 2010. View Article : Google Scholar : PubMed/NCBI
36	Shekhar TM, Miles MA, Gupte A, Taylor S, Tascone B, Walkley CR and Hawkins CJ: IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα. Oncotarget. 7:33866–33886. 2016. View Article : Google Scholar
37	Wu L, Chung JY, Cao T, Jin G, Edmiston WJ III, Hickman S, Levy ES, Whalen JA, Abrams ES, Degterev A, et al: Genetic inhibition of RIPK3 ameliorates functional outcome in controlled cortical impact independent of necroptosis. Cell Death Dis. 12:10642021. View Article : Google Scholar : PubMed/NCBI
38	Kandel S, Adhikary P, Li G and Cheng K: The TIM3/Gal9 signaling pathway: An emerging target for cancer immunotherapy. Cancer Lett. 510:67–78. 2021. View Article : Google Scholar