{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMIR135A2 is emerging as a multifaceted regulator in cancer, where its effects are highly context‐dependent. In metastatic breast cancer, for example, loss of MIR135A2 contributes to elevated Runx2 expression and increased bone metastasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In pancreatic ductal adenocarcinoma (PDAC), contrasting roles have been reported: one study found that MIR135A2 is downregulated and functions as a tumor suppressor by targeting Bmi1 to decrease cell proliferation and colony formation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ", whereas another demonstrated that MIR135A2 is upregulated in response to glutamine deprivation via mutant p53 activation, targeting phosphofructokinase‐1 to inhibit aerobic glycolysis and promote tricarboxylic acid cycle utilization."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In malignant melanoma, increased MIR135A2 expression promotes cell proliferation and tumorigenicity through direct suppression of FOXO1"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", and in models of podocyte injury, MIR135A2 (in conjunction with its homolog miR‐135b) activates Wnt/β‐catenin signaling by targeting glycogen synthase kinase‑3β, thereby perturbing cytoskeletal architecture."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Furthermore, in hepatocellular carcinoma, TGF‑β1 induces MIR135A2 expression to downregulate KLF4, leading to enhanced proliferation and metastasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In lung cancer, MIR135A2 exerts dichotomous roles; while overexpression promotes tumor progression via repression of LOXL4"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", lower serum levels of MIR135A2 are associated with distant and lymphatic metastases as well as poor prognosis in non‑small cell lung cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " A feedback circuit between MIR135A2 and ERp29 has also been observed to suppress colorectal cancer progression"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", while in gastric and gallbladder cancers, MIR135A2 regulates metastatic and proliferative processes through modulation of TRPC1"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "and angiopoietin‑2 expression"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", respectively.\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in carcinogenesis, MIR135A2 is implicated in a variety of non‑malignant conditions by modulating cell proliferation, survival, and differentiation. In the reproductive system, elevated MIR135A2 levels in granulosa cells from women with polycystic ovary syndrome suppress estrogen receptor ESR2, thereby promoting cell proliferation and correlating with higher estradiol levels."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " In vascular biology, reduced circulating MIR135A2—as influenced by the lncRNA MALAT1—disrupts NR3C2 signaling in human umbilical vein endothelial cells, impairing proliferation and apoptosis regulation and contributing to hypertension."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " Furthermore, aberrant overexpression of MIR135A2 in spermatozoa is linked to asthenozoospermia through direct targeting of JAK2"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": ", while elevated MIR135A2 levels in saliva and plasma have been identified as promising noninvasive biomarkers for endometriosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " Placental exosomal MIR135A2 also appears to contribute to gestational diabetes mellitus pathogenesis by activating the PI3K/AKT pathway via SIRT1"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": ", underscoring its potential as both a diagnostic and regulatory molecule in diverse physiological contexts.\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMIR135A2 further influences tumor cell cycle dynamics and chemoresistance. In hepatoblastoma, for instance, MIR135A2 induces the formation of a CD133‑positive cancer stem‐like subpopulation by promoting G1 phase progression and enhancing self‑renewal through activation of the Wnt/β‑catenin pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": " In gastric cancer, MIR135A2 modulates drug resistance mechanisms by directly targeting AP‑2α, which subsequently increases BCL‑2 transcription and confers resistance to apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hanna Taipaleenmäki, Gillian Browne, Jacqueline Akech, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Targeting of Runx2 by miR-135 and miR-203 Impairs Progression of Breast Cancer and Metastatic Bone Disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-14-1026"}], "href": "https://doi.org/10.1158/0008-5472.CAN-14-1026"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25634212"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25634212"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Zheng Dang, Wei-Hua Xu, Peng Lu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-135a inhibits cell proliferation by targeting Bmi1 in pancreatic ductal adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Biol Sci (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7150/ijbs.8097"}], "href": "https://doi.org/10.7150/ijbs.8097"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25013381"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25013381"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Ying Yang, Mari B Ishak Gabra, Eric A Hanse, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MiR-135 suppresses glycolysis and promotes pancreatic cancer cell adaptation to metabolic stress by targeting phosphofructokinase-1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-019-08759-0"}], "href": "https://doi.org/10.1038/s41467-019-08759-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30778058"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30778058"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Jian-Wen Ren, Zhang-Jun Li, Chen Tu "}, {"type": "b", "children": [{"type": "t", "text": "MiR-135 post-transcriptionally regulates FOXO1 expression and promotes cell proliferation in human malignant melanoma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Clin Exp Pathol (2015)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26261511"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26261511"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Xianggui Yang, Xiaoyan Wang, Fang Nie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-135 family members mediate podocyte injury through the activation of Wnt/β-catenin signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Med (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/ijmm.2015.2259"}], "href": "https://doi.org/10.3892/ijmm.2015.2259"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26134897"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26134897"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Shanshan Yao, Chuan Tian, Youcheng Ding, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Down-regulation of Krüppel-like factor-4 by microRNA-135a-5p promotes proliferation and metastasis in hepatocellular carcinoma by transforming growth factor-β1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.9934"}], "href": "https://doi.org/10.18632/oncotarget.9934"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27302923"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27302923"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Ying Zhang, Wan-Li Jiang, Jun-Yuan Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Downregulation of lysyl oxidase-like 4 LOXL4 by miR-135a-5p promotes lung cancer progression in vitro and in vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Physiol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcp.28508"}], "href": "https://doi.org/10.1002/jcp.28508"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30993701"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30993701"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Y K Zhang, B Sun, G Sui "}, {"type": "b", "children": [{"type": "t", "text": "Serum microRNA-135a downregulation as a prognostic marker of non-small cell lung cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genet Mol Res (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4238/gmr.15038252"}], "href": "https://doi.org/10.4238/gmr.15038252"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27525941"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27525941"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Carmen O N Leung, Wen Deng, Tian-Min Ye, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-135a-induced formation of CD133+ subpopulation with cancer stem cell properties in cervical cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Carcinogenesis (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/carcin/bgaa025"}], "href": "https://doi.org/10.1093/carcin/bgaa025"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32415843"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32415843"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Zhiyong Zhang, Li Ren, Qian Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TRPC1 exacerbate metastasis in gastric cancer via ciRS-7/miR-135a-5p/TRPC1 axis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2020.05.181"}], "href": "https://doi.org/10.1016/j.bbrc.2020.05.181"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32560824"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32560824"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Haiyan Diao, Xing Xu, Bin Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR‑135a‑5p inhibits tumor invasion by targeting ANGPT2 in gallbladder cancer."}]}, {"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.2021.12167"}], "href": "https://doi.org/10.3892/mmr.2021.12167"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34036386"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34036386"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Yuxia Song, Guo Yu, Yungai Xiang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Altered miR-186 and miR-135a contribute to granulosa cell dysfunction by targeting ESR2: A possible role in polycystic ovary syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Endocrinol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.mce.2019.110478"}], "href": "https://doi.org/10.1016/j.mce.2019.110478"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31173821"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31173821"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Heng Gu, Longyu Li, Bingyi Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Single nucleotide polymorphisms in binding site of miRNA-135a and targeted gene IRS2 are correlated with multiple clinical features of PCOS: A study in Chinese women."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Technol Health Care (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3233/THC-228007"}], "href": "https://doi.org/10.3233/THC-228007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35124585"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35124585"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Liju Luo, Yu Wang, Pengfei Hu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Long Non-Coding RNA Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) Promotes Hypertension by Modulating the Hsa-miR-124-3p/Nuclear Receptor Subfamily 3, Group C, Member 2 (NR3C2) and Hsa-miR-135a-5p/NR3C2 Axis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Med Sci Monit (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.12659/MSM.920478"}], "href": "https://doi.org/10.12659/MSM.920478"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32222724"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32222724"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Weiwei Li, Lei Zhang, Xiurong Yin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression of miR-135a-5p and its target gene JAK2 in spermatozoa of patients with asthenozoospermia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Andrologia (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/and.14214"}], "href": "https://doi.org/10.1111/and.14214"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34378214"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34378214"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Alexandra Perricos, Katharina Proestling, Heinrich Husslein, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hsa-mir-135a Shows Potential as A Putative Diagnostic Biomarker in Saliva and Plasma for Endometriosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomolecules (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/biom12081144"}], "href": "https://doi.org/10.3390/biom12081144"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36009038"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36009038"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Qiuyu Zhang, Xu Ye, Xia Xu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Placenta-derived exosomal miR-135a-5p promotes gestational diabetes mellitus pathogenesis by activating PI3K/AKT signalling pathway via SIRT1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jcmm.17941"}], "href": "https://doi.org/10.1111/jcmm.17941"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37667545"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37667545"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Changsheng Pu, Zhao Liu, Jianfei Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mir 135a inhibits tumor cell proliferation by regulating the expression of notch pathway in hepatoblastoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Mol Biol (Noisy-le-grand) (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.14715/cmb/2021.67.6.17"}], "href": "https://doi.org/10.14715/cmb/2021.67.6.17"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35818205"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35818205"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Yanming Pan, Fengyun Ren, Wei Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of BGC-823 cell sensitivity to adriamycin via miRNA-135a-5p."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Rep (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/or.2014.3546"}], "href": "https://doi.org/10.3892/or.2014.3546"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25322930"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25322930"}]}]}]}