CRY2 suppresses trophoblast migration and invasion in recurrent spontaneous abortion

Abstract

Disruption of circadian rhythms is associated with aberrant trophoblast migration and invasion in recurrent spontaneous abortion (RSA). This study aims to explore the functional role and the mechanisms of cryptochrome 2 (CRY2), a fundamental component of the circadian clock, in regulating trophoblast migration and invasion. Human extravillous trophoblast cell line HTR-8/SVneo was used as a cell model. Cell migration and invasion were examined using wound healing assay and Transwell assay, respectively. The mRNA and protein levels were determined using quantitative real-time polymerase chain reaction and western blot, respectively. Luciferase reporter assay and chromatin immunoprecipitation assay were performed to explore the interaction between c-Myc to the brain and muscle ARNT-like protein 1 (BMAL1) promoter. CRY2 was highly expressed in human villous specimens of RSA. Furthermore, CRY2 overexpression impaired migration and invasion in HTR-8/SVneo cells, whereas CRY2 knockdown yielded the opposite results. Mechanistically, c-Myc bound to the BMAL1 promoter and induced BMAL1 transcription, both of which further activated matrix metalloproteinase 2/9 (MMP2/9) and facilitated migration and invasion in HTR-8/SVneo cells. CRY2 inhibited c-Myc-BMAL1 pathway and impaired migration and invasion of HTR-8/SVneo cells. Collectively, these findings demonstrate that CRY2 suppresses trophoblast migration and invasion via inhibiting c-Myc-BMAL1-MMP2/9 pathway.

Tetrandrine inhibits cell migration and invasion in human nasopharyngeal carcinoma NPC‐TW 039 cells through inhibiting MAPK and RhoA signaling pathways

“…Urokinase plasminogen activator (uPA) has been shown to involve in cell mobility (Blasi & Sidenius, 2010;Tang, Hill, Brumwell, Chapman, & Wei, 2008), therefore, more studies are needed to prove in the future. The Boyden chamber system was generally used to determine the effects of TET on cell migration and invasion in vitro (Wu, Cheng, Liu, Jiang, & Yang, 2019). Thus, we used this method to show that TET at 1-10 μM after 24 hr treatment significantly suppressed the cell migration and invasion of NPC-TW 039 cells in dose-dependently (Figure 3a,b).…”

“…The Boyden chamber system was generally used to determine the effects of TET on cell migration and invasion in vitro (Wu, Cheng, Liu, Jiang, & Yang, 2019). Thus, we used this method to show that TET at 1–10 μM after 24 hr treatment significantly suppressed the cell migration and invasion of NPC‐TW 039 cells in dose‐dependently (Figure 3a,b).…”

Hypertensive disorders of pregnancy are associated with dysmenorrhea in early adulthood: A cohort study

“…Aberrant CRY2 expression suppresses proliferation and invasion of extravillous trophoblast cells, preventing normal placentation. 32 This suggests that clock gene system in the uterus plays an important role in the maintenance of pregnancy. To support the above speculation, our preliminary data demonstrated that uterine Bmal1-deficient mice failed to maintain a successful pregnancy (unpublished data).…”

“…Another group reported that cryptochrome 2 (CRY2), a transcriptional repressor that forms a core component of the circadian clock, is irregularly overexpressed in villous specimens obtained from women with recurrent spontaneous abortion. Aberrant CRY2 expression suppresses proliferation and invasion of extravillous trophoblast cells, preventing normal placentation 32 . This suggests that clock gene system in the uterus plays an important role in the maintenance of pregnancy.…”

Non-Coding RNAs Regulate Placental Trophoblast Function and Participate in Recurrent Abortion

“…Subsequently, the EVTs invade the maternal uterus, which allows the placenta to be fixed to the uterine wall, and results in the maternal spiral artery being reshaped to provide nutrition for the developing fetus. Errors at any step in this process can lead to placenta-related pathological pregnancies, including RSA (Wu et al, 2020).…”