{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMigration and invasion inhibitory protein (MIIP), also known as IIp45, is a multifunctional protein implicated in the suppression of tumor progression across a spectrum of cancers including glioma, breast, colorectal, pancreatic, renal, and others. Reduced or altered MIIP expression is associated with enhanced tumor cell proliferation, migration, invasion, and overall poor clinical outcomes, highlighting its emerging role as a tumor suppressor."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nOne important mechanism by which MIIP executes its inhibitory functions is through physical interactions with key regulatory proteins. MIIP binds to insulin‐like growth factor binding protein 2 (IGFBP2), thereby blocking IGFBP2’s invasion‐promoting effects and suppressing downstream NF‐κB signaling and adhesion molecule expression. In parallel, MIIP directly interacts with histone deacetylase 6 (HDAC6) through its catalytic domains to decrease HDAC6 stability and activity, which results in increased acetylation of α-tubulin and reduced cell motility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMIIP also plays a critical role in cell cycle regulation. In glioma models, increased MIIP expression impairs mitotic transition by binding to Cdc20 and inhibiting anaphase-promoting complex/cyclosome (APC/C)-mediated degradation of cyclin B1, which leads to mitotic catastrophe. In colorectal cancer cells, MIIP haploinsufficiency has been shown to disturb proper chromosomal segregation by affecting APC/C downstream targets—such as securin and cyclin B1—and inhibiting topoisomerase II activity, thereby promoting chromosomal instability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nUnder conditions of hypoxia, MIIP is also subjected to intricate regulatory feedback. For instance, in pancreatic cancer cells, hypoxia-inducible factor-1α (HIF-1α) upregulates a specific microRNA (miR-646) that targets the MIIP mRNA for degradation, reducing MIIP expression and consequently enhancing tumor proliferation and invasion. Moreover, MIIP can counteract hypoxia-driven accumulation of HIF-1α by inhibiting HDAC6 activity, thus promoting HIF-1α acetylation and degradation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional layers of MIIP regulation emerge from post-translational modifications and genetic variations. Epidermal growth factor (EGF) stimulation can trigger PKCε-dependent phosphorylation of MIIP at Ser303, which enhances its nuclear interaction with the NF-κB subunit RelA, preventing RelA deacetylation by HDAC6 and thereby increasing NF-κB transcriptional activity to facilitate metastasis. In breast cancer, a functional single nucleotide polymorphism (K167E) in MIIP has been associated with enhanced colony suppression capacity and a lower risk of cancer development, underscoring the significance of MIIP genetic variants in modulating its tumor suppressive functions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNotably, the clinical implications of MIIP expression appear to be context dependent. While decreased MIIP expression is linked to increased metastatic potential in glioma, colorectal cancer, and clear cell renal cell carcinoma, some studies in esophageal squamous cell carcinoma have observed higher MIIP levels correlating with poorer survival, suggesting that MIIP’s role may vary with tumor type and microenvironment. Moreover, emerging studies also propose that MIIP may influence additional signaling pathways, such as the PI3K-AKT-mTOR axis in prostate cancer and AKT-related mechanisms in hepatocellular carcinoma, and its potential involvement in endometrial carcinoma metastasis continues to be investigated."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "14"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sonya W Song, Gregory N Fuller, Asadullah Khan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IIp45, an insulin-like growth factor binding protein 2 (IGFBP-2) binding protein, antagonizes IGFBP-2 stimulation of glioma cell invasion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.2332186100"}], "href": "https://doi.org/10.1073/pnas.2332186100"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14617774"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14617774"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Sonya W Song, Gregory N Fuller, Hong Zheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inactivation of the invasion inhibitory gene IIp45 by alternative splicing in gliomas."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-04-3392"}], "href": "https://doi.org/10.1158/0008-5472.CAN-04-3392"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15867349"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15867349"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Ying Wu, Sonya W Song, Jiyuan Sun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IIp45 inhibits cell migration through inhibition of HDAC6."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109.063354"}], "href": "https://doi.org/10.1074/jbc.M109.063354"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20008322"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20008322"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yangyang Du, Ping Wang "}, {"type": "b", "children": [{"type": "t", "text": "Upregulation of MIIP regulates human breast cancer proliferation, invasion and migration by mediated by IGFBP2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pathol Res Pract (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.prp.2019.152440"}], "href": "https://doi.org/10.1016/j.prp.2019.152440"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31078343"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31078343"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "P Ji, S M Smith, Y Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inhibition of gliomagenesis and attenuation of mitotic transition by MIIP."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2010.114"}], "href": "https://doi.org/10.1038/onc.2010.114"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20418911"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20418911"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Yan Sun, Ping Ji, Tao Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MIIP haploinsufficiency induces chromosomal instability and promotes tumour progression in colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Pathol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/path.4823"}], "href": "https://doi.org/10.1002/path.4823"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27741356"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27741356"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Yi Niu, Yan Jin, Shi-Chang Deng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MiRNA-646-mediated reciprocal repression between HIF-1α and MIIP contributes to tumorigenesis of pancreatic cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41388-017-0082-2"}], "href": "https://doi.org/10.1038/s41388-017-0082-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29343850"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29343850"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Fangfang Song, Ping Ji, Hong Zheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Definition of a functional single nucleotide polymorphism in the cell migration inhibitory gene MIIP that affects the risk of breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-09-3742"}], "href": "https://doi.org/10.1158/0008-5472.CAN-09-3742"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20103646"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20103646"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Tao Chen, Jingjie Li, Meidong Xu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PKCε phosphorylates MIIP and promotes colorectal cancer metastasis through inhibition of RelA deacetylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-017-01024-2"}], "href": "https://doi.org/10.1038/s41467-017-01024-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29038521"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29038521"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Jing Wen, Qian-Wen Liu, Kong-Jia Luo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MIIP expression predicts outcomes of surgically resected esophageal squamous cell carcinomas."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Tumour Biol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s13277-015-4633-2"}], "href": "https://doi.org/10.1007/s13277-015-4633-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26825982"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26825982"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Yingmei Wang, Limei Hu, Ping Ji, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MIIP remodels Rac1-mediated cytoskeleton structure in suppression of endometrial cancer metastasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Hematol Oncol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13045-016-0342-6"}], "href": "https://doi.org/10.1186/s13045-016-0342-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27760566"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27760566"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Guang Yan, Yi Ru, Fengqi Yan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MIIP inhibits the growth of prostate cancer via interaction with PP1α and negative modulation of AKT signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Commun Signal (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12964-019-0355-1"}], "href": "https://doi.org/10.1186/s12964-019-0355-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31092266"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31092266"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "J Fang, Y-L Chen, H-B Yao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MIIP inhibits malignant progression of hepatocellular carcinoma through regulating AKT."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur Rev Med Pharmacol Sci (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.26355/eurrev_202003_20500"}], "href": "https://doi.org/10.26355/eurrev_202003_20500"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32196585"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32196585"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Fengqi Yan, Qinhao Wang, Mingyuan Xia, et al. 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