{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTENT5C (formerly known as FAM46C) is a multifunctional tumor‐suppressor gene primarily characterized in multiple myeloma. Several studies have demonstrated that its wild‐type protein functions as a non‐canonical poly(A) polymerase that enhances mRNA stability—with a strong preference for transcripts encoding endoplasmic reticulum (ER)–targeted proteins and immunoglobulins. In multiple myeloma cells, reintroduction of active TENT5C triggers broad polyadenylation and stabilization of these mRNAs, ultimately inducing ER stress and cell death. Conversely, genetic inactivation or mutation of TENT5C promotes enhanced cell proliferation, deregulates the PI3K–Akt signaling pathway, and increases cell migratory capabilities, thereby contributing to disease progression and tumor heterogeneity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its critical role in plasma cell biology, TENT5C exhibits potent tumor‐suppressive functions in several solid tumors. In hepatocellular carcinoma and gastric cancer—where its expression is typically downregulated—TENT5C upregulation has been found to inhibit cell proliferation, induce cell cycle arrest and apoptosis, and interfere with key signaling pathways such as Ras/MEK/ERK and Wnt/β‑catenin. Similarly, in osteosarcoma and esophageal squamous cell carcinoma, TENT5C expression is negatively regulated by oncomiRs (e.g. miR‑10b and miR‑1269a), and its restoration curbs invasion and migratory behavior."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMechanistically, TENT5C’s tumor‐suppressive function is further underscored by its interactions with components of protein trafficking and cell cycle regulation. It forms complexes with ER membrane–associated proteins such as FNDC3A/B to coordinate secretory capacity and autophagy, and it also physically interacts with key mitotic regulators like Polo-like kinase 4 (Plk4), inhibiting its kinase activity and preventing aberrant centriole duplication and cancer invasion. Structural studies provide insight into how mutations in TENT5C compromise its biochemical activity, offering an explanation for its tissue‑specific impact on oncogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kevin D Boyd, Fiona M Ross, Brian A Walker, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mapping of chromosome 1p deletions in myeloma identifies FAM46C at 1p12 and CDKN2C at 1p32.3 as being genes in regions associated with adverse survival."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-11-1791"}], "href": "https://doi.org/10.1158/1078-0432.CCR-11-1791"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21994415"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21994415"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yuan Xiao Zhu, Chang-Xin Shi, Laura A Bruins, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "FAM46C"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " Promotes Cell Survival in Myeloma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-16-3011"}], "href": "https://doi.org/10.1158/0008-5472.CAN-16-3011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28619709"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28619709"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Seweryn Mroczek, Justyna Chlebowska, Tomasz M Kuliński, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "FAM46C controls antibody production by the polyadenylation of immunoglobulin mRNAs and inhibits cell migration in multiple myeloma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jcmm.15078"}], "href": "https://doi.org/10.1111/jcmm.15078"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32141701"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32141701"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Jo Kanasugi, Ichiro Hanamura, Akinobu Ota, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Biallelic loss of FAM46C triggers tumor growth with concomitant activation of Akt signaling in multiple myeloma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Sci (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cas.14386"}], "href": "https://doi.org/10.1111/cas.14386"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32176823"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32176823"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Nicola Manfrini, Marilena Mancino, Annarita Miluzio, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FAM46C and FNDC3A Are Multiple Myeloma Tumor Suppressors That Act in Concert to Impair Clearing of Protein Aggregates and Autophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-20-1357"}], "href": "https://doi.org/10.1158/0008-5472.CAN-20-1357"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32963011"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32963011"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Weilong Zhang, Chaoling Wu, Shuang Geng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FAM46C-mediated tumor heterogeneity predicts extramedullary metastasis and poorer survival in multiple myeloma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Aging (Albany NY) (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/aging.204697"}], "href": "https://doi.org/10.18632/aging.204697"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37155154"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37155154"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Qiao-Yan Zhang, Xiao-Qiang Yue, Yi-Ping Jiang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FAM46C is critical for the anti-proliferation and pro-apoptotic effects of norcantharidin in hepatocellular carcinoma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-017-00313-6"}], "href": "https://doi.org/10.1038/s41598-017-00313-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28341836"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28341836"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Jun Shi, Qiuwei Zhu, Jianbo Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FAM46C suppresses gastric cancer by inhibition of Wnt/beta-catenin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Biosci (Landmark Ed) (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2741/4820"}], "href": "https://doi.org/10.2741/4820"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31585903"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31585903"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Xue-Zhu Gao, Xiu-Feng Xi, Shi-Ping Zhang "}, {"type": "b", "children": [{"type": "t", "text": "Down-regulation of miR-10b represses cell vitality in osteosarcoma and is inversely associated with prognosis via interacting with FAM46C: Running title: MiR-10b/FAM46C axis modulates OS progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Tissue Cell (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.tice.2020.101331"}], "href": "https://doi.org/10.1016/j.tice.2020.101331"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32223957"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32223957"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Yuefeng Ma, Xin Xing, Chuantao Cheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hsa-miR-1269a up-regulation fosters the malignant progression of esophageal squamous cell carcinoma via targeting FAM46C."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mutat Res (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.mrfmmm.2023.111832"}], "href": "https://doi.org/10.1016/j.mrfmmm.2023.111832"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37467675"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37467675"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Karineh Kazazian, Yosr Haffani, Deanna Ng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FAM46C/TENT5C functions as a tumor suppressor through inhibition of Plk4 activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Commun Biol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s42003-020-01161-3"}], "href": "https://doi.org/10.1038/s42003-020-01161-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32807875"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32807875"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Chiara Fucci, Massimo Resnati, Elena Riva, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Interaction of the Tumor Suppressor FAM46C with p62 and FNDC3 Proteins Integrates Protein and Secretory Homeostasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2020.108162"}], "href": "https://doi.org/10.1016/j.celrep.2020.108162"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32966780"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32966780"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Hong Zhang, Shi-Hui Zhang, Jia-Li Hu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural and functional characterization of multiple myeloma associated cytoplasmic poly(A) polymerase FAM46C."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Commun (Lond) (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cac2.12163"}], "href": "https://doi.org/10.1002/cac2.12163"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34048638"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34048638"}]}]}]}