LHPP

Major depressive disorder (MDD) is a widespread mental health condition that for many is disabling. It has long been appreciated that MDD has genetic as well as environmental influences. In a new study researchers identify a gene that interacted with stress to mediate aspects of treatment-resistant MDD in an animal model. Major depressive disorder (MDD) is a widespread mental health condition that for many is disabling. It has long been appreciated that MDD has genetic as well as environmental influences. In a new study in Biological Psychiatry, published by Elsevier, researchers identify a gene that interacted with stress to mediate aspects of treatment-resistant MDD in an animal model. Jing Zhang, PhD, at Fujian Medical University and senior author of the study, said, "Emerging evidence suggests that MDD is a consequence of the co-work of genetic risks and environmental factors, so it is crucial to explore how stress exposure and risk genes co-contribute to the pathogenesis of MDD." To do that, the authors used a mouse model of stress-induced depression called chronic social defeat stress (CSDS) in which mice are exposed to aggressor mice daily for two weeks. They focused on a gene called LHPP, which interacts with other signaling molecules at neuronal synapses. Increased expression of LHPP in the stressed mice aggravated the depression-like behaviors by decreasing expression of BDNF and PSD95 by dephosphorylating two protein kinases, CaMKIIα and ERK, under stress exposure. Dr. Zhang noted, "Interestingly, LHPP mutations (E56K, S57L) in humans can enhance CaMKIIα/ERK-BDNF/PSD95 signaling, which suggests that carrying LHPP mutations may have an antidepressant effect in the population." MDD is an extremely heterogeneous condition. Differences in the types of depression experienced by people influence the way they respond to treatment. A large subgroup of people with depression fail to respond to standard antidepressant medications and have "treatment-resistant" symptoms of depression. These patients often respond to different medications, such as ketamine or esketamine, or to electroconvulsive therapy. Notably, esketamine markedly alleviated LHPP-induced depression-like behaviors, whereas the traditional drug fluoxetine did not, suggesting that the mechanism might underlie some types of treatment-resistant depression. John Krystal, MD, Editor of Biological Psychiatry, said of the work, "We have limited understanding of the neurobiology of treatment-resistant forms of depression. This study identifies a depression risk mechanism for stress-related behaviors that fail to respond to a standard antidepressant but respond well to ketamine. This may suggest that the risk mechanisms associated with the LHPP gene shed light on the poorly understood biology of treatment-resistant forms of depression." Dr. Zhang added, "Together, our findings identify LHPP as an essential player driving stress-induced depression, implying targeting LHPP as an effective strategy in MDD therapeutics in the future."

结直肠癌(CRC)是全球第三大常见恶性肿瘤，也是全球第二大癌症相关死亡原因。结直肠癌的发病率不断增加，据估计，2020年约有190万例新发结直肠癌病例，93.5万人死亡。 结直肠癌(CRC)是全球第三大常见恶性肿瘤，也是全球第二大癌症相关死亡原因。结直肠癌的发病率不断增加，据估计，2020年约有190万例新发结直肠癌病例，93.5万人死亡。CRC的分子发病机制尚未完全阐明，在提高CRC患者的生存率方面也取得了有限的成功。因此，需要不断的努力来阐明潜在的分子机制和识别新的治疗靶点。 图片来源：https://doi-org.libproxy1.nus.edu.sg/10.1186/s12943-022-01675-w 近日，来自江南大学附属医院的研究者们在Molecular Cancer杂志上发表了题为“Long noncoding RNA DLGAP1-AS2 promotes tumorigenesis and metastasis by regulating the Trim21/ELOA/LHPP axis in colorectal cancer”的文章，该研究表明DLGAP1-AS2是一种很有前途的预后生物标志物，它的发现揭示了结直肠癌分子发病机制的新维度，并为结直肠癌的治疗提供了一个新的靶点。 长非编码RNA(LncRNAs)推动了研究，重点是它们作为癌基因或参与癌症发生的肿瘤抑制因子的作用。然而，大多数LncRNAs在结直肠癌(CRC)中的功能和机制仍不清楚。 研究者用定量RT-PCR方法检测DLGAP1-AS2在多个结直肠癌队列中的表达。通过一系列体外和体内实验评价DLGAP1-AS2对结直肠癌生长和转移的影响。此外，通过RNA下拉、RNA免疫沉淀、RNA测序、荧光素酶测定、染色质免疫沉淀和挽救实验，揭示了DLGAP1-AS2在结直肠癌中的作用机制。 研究者发现DLGAP1-AS2通过与Elongin A(Elongin A，Elongin A)的物理相互作用促进肿瘤的发生和转移，并通过促进含有21(Trim21)的三个基序(Trim21)介导的泛素化修饰和ELOA的降解来抑制其蛋白质稳定性，从而促进肿瘤的发生和转移。 特别是，研究者发现DLGAP1-AS2通过抑制ELOA介导的LHPP的转录激活，从而阻断LHPP依赖的AKT信号通路，从而降低LHPP的表达。此外，研究者还证明了DLGAP1-AS2被切割和多聚腺苷化特异性因子(CPSF2)和切割刺激因子(CSTF3)结合并稳定。 CPSF2和CSTF3可提高DLGAP1-AS2在结直肠癌细胞中的稳定性 图片来源：https://doi-org.libproxy1.nus.edu.sg/10.1186/s12943-022-01675-w 综上所述，研究者证明了DLGAP1-AS2通过促进肿瘤生长和转移而在结直肠癌中作为致癌的lncRNA发挥作用。机制上，DLGAP1-AS2通过促进Trim21介导的泛素化和ELOA的降解来抑制ELOA蛋白的稳定性。 研究者还证明了ELOA通过与其启动子结合来增强LHPP的转录，从而揭示了DLGAP1-AS2/Trim21/ELOA/LHPP在结直肠癌中的一个新的调节轴。此外，研究者还发现CPSF2和CSTF3与DLGAP1AS2结合并增加其稳定性。这些数据为结直肠癌的发生提供了洞察力，并表明DLGAP1-AS2是一种有前途的预后生物标志物和结直肠癌的治疗靶点（生物谷 Bioon.com） 参考文献 Xue Wang et al. Long noncoding RNA DLGAP1-AS2 promotes tumorigenesis and metastasis by regulating the Trim21/ELOA/LHPP axis in colorectal cancer. Mol Cancer. 2022 Nov 14;21(1):210. doi: 10.1186/s12943-022-01675-w.