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Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Research Article

Prognostic and Immunological Significance of Rhomboid Domain Containing Protein 1 in Multiple Primary Cancers

Author(s): Tongbo Wang, Xiaojie Zhang, Wenjie Liu, Chongyuan Sun, Zefeng Li and Dongbing Zhao*

Volume 26, Issue 4, 2023

Published on: 26 September, 2022

Page: [682 - 695] Pages: 14

DOI: 10.2174/1386207325666220609120001

Price: $65

Abstract

Background: RHBDD1 is an intramembrane serine protease of the rhomboid superfamily that regulates diverse physiological and pathological processes. However, the relationship between RHBDD1 expression, tumor-infiltrating immune cells (TIICs), and cancer prognosis remains unclear.

Objective: We comprehensively analyzed the prognostic and immunological significance of RHBDD1 in multiple primary cancers.

Methods: RHBDD1 expression was investigated using Oncomine, TIMER, and UALCAN databases, after which the clinical prognostic value of RHBDD1 was assessed with online public databases. In addition, we explored the correlation between RHBDD1 and TIICs by TIMER and GEPIA and investigated the relationship between RHBDD1 expression and chemokines in cancers by TIMER.

Results: In general, compared to that in adjacent normal tissue, lower expression of RHBDD1 was found in various cancers and was correlated to pathological stages. Although RHBDD1 showed a protective effect on multiple solid tumors, a high expression level of RHBDD1 was detrimental to the survival of stomach adenocarcinoma patients. RHBDD1 was positively correlated to immune infiltration levels in various cancers, including lung, breast, ovarian, and gastric cancer. Furthermore, gene markers of TIICs, such as tumor-associated macrophages (TAMs), dendritic cells (DCs), and regulatory T cells, were also correlated to RHBDD1 expression. In addition, the RHBDD1 expression level was positively correlated to multiple chemokines in cancers, which could recruit diverse immune cells at the tumor site.

Conclusions: RHBDD1, which correlates with immune infiltration, can be used as a potential prognostic biomarker in multiple primary cancers. Specifically, RHBDD1 expression potentially contributes to the recruitment of TAMs and DCs and the regulation of T cell functions in cancers.

Keywords: Rhomboid domain-containing protein 1, tumor microenvironment, immune infiltration, prognosis, primary cancer, fibroblasts.

[1]
Wu, T.; Dai, Y. Tumor microenvironment and therapeutic response. Cancer Lett., 2017, 387, 61-68.
[http://dx.doi.org/10.1016/j.canlet.2016.01.043] [PMID: 26845449]
[2]
Beatty, G.L.; Gladney, W.L. Immune escape mechanisms as a guide for cancer immunotherapy. Clin. Cancer Res., 2015, 21(4), 687-692.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-1860] [PMID: 25501578]
[3]
Giraldo, N.A.; Sanchez-Salas, R.; Peske, J.D.; Vano, Y.; Becht, E.; Petitprez, F.; Validire, P.; Ingels, A.; Cathelineau, X.; Fridman, W.H.; Sautès-Fridman, C. The clinical role of the TME in solid cancer. Br. J. Cancer, 2019, 120(1), 45-53.
[http://dx.doi.org/10.1038/s41416-018-0327-z] [PMID: 30413828]
[4]
Badalamenti, G.; Fanale, D.; Incorvaia, L.; Barraco, N.; Listì, A.; Maragliano, R.; Vincenzi, B.; Calò, V.; Iovanna, J.L.; Bazan, V.; Russo, A. Role of tumor-infiltrating lymphocytes in patients with solid tumors: Can a drop dig a stone? Cell. Immunol., 2019, 343, 103753.
[http://dx.doi.org/10.1016/j.cellimm.2018.01.013] [PMID: 29395859]
[5]
Topalian, S.L.; Drake, C.G.; Pardoll, D.M. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell, 2015, 27(4), 450-461.
[http://dx.doi.org/10.1016/j.ccell.2015.03.001] [PMID: 25858804]
[6]
Gordon, S.R.; Maute, R.L.; Dulken, B.W.; Hutter, G.; George, B.M.; McCracken, M.N.; Gupta, R.; Tsai, J.M.; Sinha, R.; Corey, D.; Ring, A.M.; Connolly, A.J.; Weissman, I.L. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature, 2017, 545(7655), 495-499.
[http://dx.doi.org/10.1038/nature22396] [PMID: 28514441]
[7]
Garon, E.B.; Rizvi, N.A.; Hui, R.; Leighl, N.; Balmanoukian, A.S.; Eder, J.P.; Patnaik, A.; Aggarwal, C.; Gubens, M.; Horn, L.; Carcereny, E.; Ahn, M.J.; Felip, E.; Lee, J.S.; Hellmann, M.D.; Hamid, O.; Goldman, J.W.; Soria, J.C.; Dolled-Filhart, M.; Rutledge, R.Z.; Zhang, J.; Lunceford, J.K.; Rangwala, R.; Lubiniecki, G.M.; Roach, C.; Emancipator, K.; Gandhi, L. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med., 2015, 372(21), 2018-2028.
[http://dx.doi.org/10.1056/NEJMoa1501824] [PMID: 25891174]
[8]
Urban, S.; Dickey, S.W. The rhomboid protease family: a decade of progress on function and mechanism. Genome Biol., 2011, 12(10), 231.
[http://dx.doi.org/10.1186/gb-2011-12-10-231] [PMID: 22035660]
[9]
Tichá, A.; Collis, B.; Strisovsky, K. The rhomboid superfamily: structural mechanisms and chemical biology opportunities. Trends Biochem. Sci., 2018, 43(9), 726-739.
[http://dx.doi.org/10.1016/j.tibs.2018.06.009] [PMID: 30055896]
[10]
Wang, Y.; Guan, X.; Fok, K.L.; Li, S.; Zhang, X.; Miao, S.; Zong, S.; Koide, S.S.; Chan, H.C.; Wang, L. A novel member of the Rhomboid family, RHBDD1, regulates BIK-mediated apoptosis. Cell. Mol. Life Sci., 2008, 65(23), 3822-3829.
[http://dx.doi.org/10.1007/s00018-008-8452-0] [PMID: 18953687]
[11]
Wan, C.; Fu, J.; Wang, Y.; Miao, S.; Song, W.; Wang, L. Exosome-related multi-pass transmembrane protein TSAP6 is a target of rhomboid protease RHBDD1-induced proteolysis. PLoS One, 2012, 7(5), e37452.
[http://dx.doi.org/10.1371/journal.pone.0037452] [PMID: 22624035]
[12]
Fleig, L.; Bergbold, N.; Sahasrabudhe, P.; Geiger, B.; Kaltak, L.; Lemberg, M.K. Ubiquitin-dependent intramembrane rhomboid protease promotes ERAD of membrane proteins. Mol. Cell, 2012, 47(4), 558-569.
[http://dx.doi.org/10.1016/j.molcel.2012.06.008] [PMID: 22795130]
[13]
Wunderle, L.; Knopf, J.D.; Kühnle, N.; Morlé, A.; Hehn, B.; Adrain, C.; Strisovsky, K.; Freeman, M.; Lemberg, M.K. Rhomboid intramembrane protease RHBDL4 triggers ER-export and non-canonical secretion of membrane-anchored TGFα. Sci. Rep., 2016, 6, 27342.
[http://dx.doi.org/10.1038/srep27342] [PMID: 27264103]
[14]
Zhang, M.; Miao, F.; Huang, R.; Liu, W.; Zhao, Y.; Jiao, T.; Lu, Y.; Wu, F.; Wang, X.; Wang, H.; Zhao, H.; Ju, H.; Miao, S.; Wang, L.; Song, W. Correction to: RHBDD1 promotes colorectal cancer metastasis through the Wnt signaling pathway and its downstream target ZEB1. J. Exp. Clin. Cancer Res., 2018, 37(1), 60.
[http://dx.doi.org/10.1186/s13046-018-0709-3] [PMID: 29548344]
[15]
Song, W.; Liu, W.; Zhao, H.; Li, S.; Guan, X.; Ying, J.; Zhang, Y.; Miao, F.; Zhang, M.; Ren, X.; Li, X.; Wu, F.; Zhao, Y.; Tian, Y.; Wu, W.; Fu, J.; Liang, J.; Wu, W.; Liu, C.; Yu, J.; Zong, S.; Miao, S.; Zhang, X.; Wang, L. Rhomboid domain containing 1 promotes colorectal cancer growth through activation of the EGFR signalling pathway. Nat. Commun., 2015, 6, 8022.
[http://dx.doi.org/10.1038/ncomms9022] [PMID: 26300397]
[16]
Han, J.; Bai, J.; Yang, Y.; Yin, H.; Gao, W.; Lu, A.; Liu, F.; Ge, H.; Liu, Z.; Wang, J.; Zhong, L. Lentivirus-mediated knockdown of rhomboid domain containing 1 inhibits colorectal cancer cell growth. Mol. Med. Rep., 2015, 12(1), 377-381.
[http://dx.doi.org/10.3892/mmr.2015.3365] [PMID: 25695376]
[17]
Zhang, X.; Zhao, Y.; Wang, C.; Ju, H.; Liu, W.; Zhang, X.; Miao, S.; Wang, L.; Sun, Q.; Song, W. Rhomboid domain-containing protein 1 promotes breast cancer progression by regulating the p-Akt and CDK2 levels. Cell Commun. Signal., 2018, 16(1), 65.
[http://dx.doi.org/10.1186/s12964-018-0267-5] [PMID: 30286765]
[18]
Rhodes, D.R.; Yu, J.; Shanker, K.; Deshpande, N.; Varambally, R.; Ghosh, D.; Barrette, T.; Pandey, A.; Chinnaiyan, A.M. ONCOMINE: A cancer microarray database and integrated data-mining platform. Neoplasia, 2004, 6(1), 1-6.
[http://dx.doi.org/10.1016/S1476-5586(04)80047-2] [PMID: 15068665]
[19]
Chandrashekar, D.S.; Bashel, B.; Balasubramanya, S.A.H.; Creighton, C.J.; Ponce-Rodriguez, I.; Chakravarthi, B.V.S.K.; Varambally, S. UALCAN: A portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia, 2017, 19(8), 649-658.
[http://dx.doi.org/10.1016/j.neo.2017.05.002] [PMID: 28732212]
[20]
Mizuno, H.; Kitada, K.; Nakai, K.; Sarai, A. PrognoScan: a new database for meta-analysis of the prognostic value of genes. BMC Med. Genomics, 2009, 2, 18.
[http://dx.doi.org/10.1186/1755-8794-2-18] [PMID: 19393097]
[21]
Li, T.; Fan, J.; Wang, B.; Traugh, N.; Chen, Q.; Liu, J.S.; Li, B.; Liu, X.S. TIMER: A web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res., 2017, 77(21), e108-e110.
[http://dx.doi.org/10.1158/0008-5472.CAN-17-0307] [PMID: 29092952]
[22]
Li, T.; Fu, J.; Zeng, Z.; Cohen, D.; Li, J.; Chen, Q.; Li, B.; Liu, X.S. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res., 2020, 48(W1), W509-W514.
[http://dx.doi.org/10.1093/nar/gkaa407] [PMID: 32442275]
[23]
Danaher, P.; Warren, S.; Dennis, L.; D’Amico, L.; White, A.; Disis, M.L.; Geller, M.A.; Odunsi, K.; Beechem, J.; Fling, S.P. Gene expression markers of Tumor Infiltrating Leukocytes. J. Immunother. Cancer, 2017, 5, 18.
[http://dx.doi.org/10.1186/s40425-017-0215-8] [PMID: 28239471]
[24]
Sousa, S.; Määttä, J. The role of tumour-associated macrophages in bone metastasis. J. Bone Oncol., 2016, 5(3), 135-138.
[http://dx.doi.org/10.1016/j.jbo.2016.03.004] [PMID: 27761375]
[25]
Gu, Y.; Li, X.; Bi, Y.; Zheng, Y.; Wang, J.; Li, X.; Huang, Z.; Chen, L.; Huang, Y.; Huang, Y. CCL14 is a prognostic biomarker and correlates with immune infiltrates in hepatocellular carcinoma. Aging (Albany NY), 2020, 12(1), 784-807.
[http://dx.doi.org/10.18632/aging.102656] [PMID: 31927532]
[26]
Tang, Z.; Li, C.; Kang, B.; Gao, G.; Li, C.; Zhang, Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res., 2017, 45(W1), W98-W102.
[http://dx.doi.org/10.1093/nar/gkx247] [PMID: 28407145]
[27]
Santoiemma, P.P.; Powell, D.J., Jr. Tumor infiltrating lymphocytes in ovarian cancer. Cancer Biol. Ther., 2015, 16(6), 807-820.
[http://dx.doi.org/10.1080/15384047.2015.1040960] [PMID: 25894333]
[28]
Bremnes, R.M.; Busund, L.T.; Kilvær, T.L.; Andersen, S.; Richardsen, E.; Paulsen, E. E.; Hald, S.; Khanehkenari, M. R.; Cooper, W. A.; Kao, S. C.; Dønnem, T. The role of tumor-infiltrating lymphocytes in development, progression, and prognosis of non-small cell lung cancer. J. Thoracic Oncol., 2016, 11(6), 789-800.
[29]
Stanton, S.E.; Disis, M.L. Clinical significance of tumor-infiltrating lymphocytes in breast cancer. J. Immunother. Cancer, 2016, 4, 59.
[http://dx.doi.org/10.1186/s40425-016-0165-6] [PMID: 27777769]
[30]
Ohue, Y.; Nishikawa, H.; Regulatory, T. Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target? Cancer Sci., 2019, 110(7), 2080-2089.
[http://dx.doi.org/10.1111/cas.14069] [PMID: 31102428]
[31]
Balkwill, F.R. The chemokine system and cancer. J. Pathol., 2012, 226(2), 148-157.
[http://dx.doi.org/10.1002/path.3029] [PMID: 21989643]
[32]
Caronni, N.; Savino, B.; Bonecchi, R. Myeloid cells in cancer-related inflammation. Immunobiology, 2015, 220(2), 249-253.
[http://dx.doi.org/10.1016/j.imbio.2014.10.001] [PMID: 25454487]
[33]
Wendel, M.; Galani, I.E.; Suri-Payer, E.; Cerwenka, A. Natural killer cell accumulation in tumors is dependent on IFN-gamma and CXCR3 ligands. Cancer Res., 2008, 68(20), 8437-8445.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-1440] [PMID: 18922917]
[34]
Hensbergen, P.J.; Wijnands, P.G.; Schreurs, M.W.; Scheper, R.J.; Willemze, R.; Tensen, C. P. The CXCR3 targeting chemokine CXCL11 has potent antitumor activity in vivo involving attraction of CD8+ T lymphocytes but not inhibition of angiogenesis. Journal of immunotherapy (Hagerstown, Md. : 1997), 2005, 28(4), 343-351.
[35]
Gobert, M.; Treilleux, I.; Bendriss-Vermare, N.; Bachelot, T.; Goddard-Leon, S.; Arfi, V.; Biota, C.; Doffin, A.C.; Durand, I.; Olive, D.; Perez, S.; Pasqual, N.; Faure, C.; Ray-Coquard, I.; Puisieux, A.; Caux, C.; Blay, J.Y.; Ménétrier-Caux, C. Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res., 2009, 69(5), 2000-2009.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-2360] [PMID: 19244125]
[36]
Scarpino, S.; Stoppacciaro, A.; Ballerini, F.; Marchesi, M.; Prat, M.; Stella, M.C.; Sozzani, S.; Allavena, P.; Mantovani, A.; Ruco, L.P. Papillary carcinoma of the thyroid: hepatocyte growth factor (HGF) stimulates tumor cells to release chemokines active in recruiting dendritic cells. Am. J. Pathol., 2000, 156(3), 831-837.
[http://dx.doi.org/10.1016/S0002-9440(10)64951-6] [PMID: 10702399]
[37]
Correale, P.; Rotundo, M.S.; Botta, C.; Del Vecchio, M.T.; Tassone, P.; Tagliaferri, P. Tumor infiltration by chemokine receptor 7 (CCR7)(+) T-lymphocytes is a favorable prognostic factor in metastatic colorectal cancer. OncoImmunology, 2012, 1(4), 531-532.
[http://dx.doi.org/10.4161/onci.19404] [PMID: 22754775]
[38]
Mburu, Y.K.; Wang, J.; Wood, M.A.; Walker, W.H.; Ferris, R.L. CCR7 mediates inflammation-associated tumor progression. Immunol. Res., 2006, 36(1-3), 61-72.
[http://dx.doi.org/10.1385/IR:36:1:61] [PMID: 17337767]
[39]
Al-Salihi, M.A.; Lang, P.A. iRhom2: An emerging adaptor regulating immunity and disease. Int. J. Mol. Sci., 2020, 21(18), E6570.
[http://dx.doi.org/10.3390/ijms21186570] [PMID: 32911849]
[40]
Luo, W.W.; Shu, H.B. Emerging roles of rhomboid-like pseudoproteases in inflammatory and innate immune responses. FEBS Lett., 2017, 591(20), 3182-3189.
[http://dx.doi.org/10.1002/1873-3468.12796] [PMID: 28815577]

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