Long noncoding RNA (lncRNA) metallothionein 1 J, pseudogene (MT1JP) is downregulated in triple-negative breast cancer and upregulates microRNA-138 (miR-138) to downregulate hypoxia-inducible factor-1α (HIF-1α)

Triple-negative breast cancer (TNBC) is a highly invasive subtype of breast cancer. This study explored the molecular mechanism and influences of metallothionein 1 J, pseudogene (MT1JP), microRNA-138 (miR-138), and hypoxia-inducible factor-1α (HIF-1α) on TNBC cell proliferation and migration. We confirmed TNBC cases by immunohistochemistry (IHC) staining. The expression of MT1JP in two types of tissue collected from 78 TNBC patients was detected by performing real-time quantitative fluorescence PCR (RT-qPCR). To further evaluate the relationship among MT1JP, miR-138 and HIF-1α, expression vectors of MT1JP and HIF-1α, as well as miR-138 mimic and inhibitor, were delivered into BT-549 cells. We observed that MT1JP was downregulated in TNBC. MT1JP was positively correlated with miR-138 but negatively correlated with HIF-1α in TNBC tissues. In TNBC cells, upregulation of miR-138 and downregulation of HIF-1α were observed after overexpression of MT1JP. In addition, overexpression of miR-138 resulted in downregulation of HIF-1α but did not affect the expression of MT1JP. Decreased proliferation rate of TNBC cells was observed after overexpression of MT1JP and miR-138. HIF-1α increased cell proliferation and migration. HIF-1α also suppressed the role of MT1JP and miR-138 in TNBC cell proliferation and migration. In conclusion, our findings demonstrated that MT1JP inhibited TNBC by regulating the miR-138/HIF-1α axis, indicating that MT1JP might serve as a biomarker or target for TNBC treatment.

三阴性乳腺癌（Triple-negative breast cancer, TNBC）是一类侵袭性极强的乳腺癌亚型。本研究探讨了金属硫蛋白1J假基因（metallothionein 1 J pseudogene, MT1JP）、微小RNA-138（microRNA-138, miR-138）以及缺氧诱导因子-1α（hypoxia-inducible factor-1α, HIF-1α）对TNBC细胞增殖与迁移的分子机制及影响。本研究通过免疫组化（immunohistochemistry, IHC）染色确认TNBC病例，采集78例TNBC患者的两类组织，采用实时荧光定量聚合酶链式反应（real-time quantitative fluorescence PCR, RT-qPCR）检测MT1JP在其中的表达水平。为进一步探究MT1JP、miR-138与HIF-1α之间的调控关系，本研究将MT1JP与HIF-1α的表达载体，以及miR-138模拟物和抑制剂转染至BT-549细胞中。研究观察到，MT1JP在TNBC组织中呈低表达状态；TNBC组织内，MT1JP与miR-138呈正相关，而与HIF-1α呈负相关。在TNBC细胞中，过表达MT1JP可使miR-138表达上调、HIF-1α表达下调。此外，过表达miR-138可导致HIF-1α表达降低，但对MT1JP的表达无显著影响。过表达MT1JP与miR-138后，TNBC细胞的增殖速率显著降低。HIF-1α可促进细胞增殖与迁移，同时还能拮抗MT1JP与miR-138对TNBC细胞增殖及迁移的调控作用。综上，本研究证实MT1JP通过调控miR-138/HIF-1α轴发挥抑癌作用，提示MT1JP可作为TNBC诊疗的生物标志物或治疗靶点。