{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRHBDD1 is an intramembrane serine protease belonging to the rhomboid family that plays a key role in regulating apoptosis and tumor cell proliferation. Early studies demonstrated that RHBDD1 can cleave BIK, a pro‑apoptotic Bcl‑2 family member, thereby modulating cell death pathways. In glioblastoma cells, for example, silencing RHBDD1 markedly reduced cell proliferation and colony formation, consistent with its function as a positive regulator of tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRHBDD1 also impacts key oncogenic signaling pathways. It has been shown to enhance the activity of the AP‑1 transcription factor—upregulating c‑Jun and its downstream targets such as Bcl‑3—which contributes to the inhibition of apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In colorectal cancer, RHBDD1 promotes EGFR expression via the AP‑1 pathway and is linked to tumor metastasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Moreover, microRNA‑mediated downregulation of RHBDD1 (e.g. by miR‑145‑5p) has been shown to inhibit cell proliferation, invasion, and migration by suppressing the EGFR/Raf/MEK/ERK cascade in colorectal cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Similar pro‑tumorigenic effects of RHBDD1 have been reported in non‑small cell lung cancer, where its expression promotes cell cycle progression and survival"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", as well as in pancreatic adenocarcinoma through activation of the AKT/β‑catenin pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional work has revealed that RHBDD1 participates in the regulation of exosomal trafficking by proteolytically processing TSAP6, a multi‑pass transmembrane protein involved in non‑classical secretion pathways; this cleavage affects the release of exosome‐associated apoptotic factors."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Collectively, these studies—as well as emerging evidence linking RHBDD1 expression to tumor‑infiltrating immune cells and adverse prognosis in various cancers"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "—underscore the multifunctional nature of RHBDD1 in promoting tumor progression and highlight its potential as a therapeutic target.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Y Wang, X Guan, K L Fok, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A novel member of the Rhomboid family, RHBDD1, regulates BIK-mediated apoptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Mol Life Sci (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00018-008-8452-0"}], "href": "https://doi.org/10.1007/s00018-008-8452-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18953687"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18953687"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Xue-Ni Liu, Zheng-Hao Tang, Yi Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Lentivirus-mediated silencing of rhomboid domain containing 1 suppresses tumor growth and induces apoptosis in hepatoma HepG2 cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Asian Pac J Cancer Prev (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7314/apjcp.2013.14.1.5"}], "href": "https://doi.org/10.7314/apjcp.2013.14.1.5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23534782"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23534782"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Xiaoxia Ren, Wei Song, Wenjie Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Rhomboid domain containing 1 inhibits cell apoptosis by upregulating AP-1 activity and its downstream target Bcl-3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2013.04.033"}], "href": "https://doi.org/10.1016/j.febslet.2013.04.033"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23669365"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23669365"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Fei Miao, Mengmeng Zhang, Yuechao Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RHBDD1 upregulates EGFR via the AP-1 pathway in colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.15694"}], "href": "https://doi.org/10.18632/oncotarget.15694"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28445956"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28445956"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Mengmeng Zhang, Fei Miao, Rong Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RHBDD1 promotes colorectal cancer metastasis through the Wnt signaling pathway and its downstream target ZEB1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Clin Cancer Res (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13046-018-0687-5"}], "href": "https://doi.org/10.1186/s13046-018-0687-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29426364"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29426364"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Ying Niu, Jinping Zhang, Yalin Tong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-145-5p restrained cell growth, invasion, migration and tumorigenesis via modulating RHBDD1 in colorectal cancer via the EGFR-associated signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Biochem Cell Biol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.biocel.2019.105641"}], "href": "https://doi.org/10.1016/j.biocel.2019.105641"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31693935"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31693935"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Suyan Xu, Hongyan Zhang, Aifeng Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Silibinin suppresses epithelial-mesenchymal transition in human non-small cell lung cancer cells by restraining RHBDD1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Mol Biol Lett (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s11658-020-00229-6"}], "href": "https://doi.org/10.1186/s11658-020-00229-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32528541"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32528541"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Zhe-Yuan Xu, Xu Li, Rui-Hong Yao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Rhomboid domain containing 1 promotes the growth of non-small cell lung cancer through the activation of EGFR and regulation of the BIK-mediated apoptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neoplasma (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4149/neo_2021_210804N1107"}], "href": "https://doi.org/10.4149/neo_2021_210804N1107"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34962825"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34962825"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Mingyang Li, Licheng Cai, Xingyuan Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RHBDD1 promotes proliferation, migration, invasion and EMT in renal cell carcinoma via the EGFR/AKT signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Med Rep (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/mmr.2021.12466"}], "href": "https://doi.org/10.3892/mmr.2021.12466"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34581421"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34581421"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Chunhua Wan, Jun Fu, Yong Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Exosome-related multi-pass transmembrane protein TSAP6 is a target of rhomboid protease RHBDD1-induced proteolysis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0037452"}], "href": "https://doi.org/10.1371/journal.pone.0037452"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22624035"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22624035"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Tongbo Wang, Xiaojie Zhang, Wenjie Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prognostic and Immunological Significance of Rhomboid Domain Containing Protein 1 in Multiple Primary Cancers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Comb Chem High Throughput Screen (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2174/1386207325666220609120001"}], "href": "https://doi.org/10.2174/1386207325666220609120001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35692140"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35692140"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Yingxue Yang, Yuan Yuan, Boning Xia "}, {"type": "b", "children": [{"type": "t", "text": "RHBDD1 Promotes the Growth and Stemness Characteristics of Gastric Cancer Cells by Activating Wnt/β-catenin Signaling Pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Curr Stem Cell Res Ther (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2174/011574888X259932231010112521"}], "href": "https://doi.org/10.2174/011574888X259932231010112521"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37861049"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37861049"}]}]}]}