ESRRB Inhibits the TGFß Signaling Pathway to Drive Cell Proliferation in Cervical Cancer.

Estrogen-related receptor ß (ESRRB) is a member of the orphan nuclear receptor family and mediates stem cell self-renewal and early embryonic development. Previous studies have also reported that ESRRB plays a role in the development and progression of breast cancer and prostate cancer. In this study, we observed that ESRRB was highly expressed in cervical cancer and was associated with disease progression. Knocking out ESRRB using CRISPR/Cas9 gene editing in cervical cancer cells induced cell-cycle arrest at the transition from the G0-G1 phase to the S phase, resulting in inhibition of cell proliferation in vitro and reduced tumor growth in vivo. Conversely, ectopic expression of ESRRB significantly promoted the proliferation of cervical cancer cells. ESRRB activated transcription of SMAD7, a TGFß pathway inhibitor, which blocked phosphorylation and nuclear translocation of SMAD2/3 to the nucleus, thereby downregulating CDKN1A and upregulating CCNA2 and MYC. In turn, MYC transactivated ESRRB and upregulated SMAD7, thus forming a positive feedback loop with ESRRB. Together, these findings identify the tumor-promoting function of ESRRB in cervical cancer and reveal a mechanism by which ESRRB stimulates cell proliferation to promote cancer progression. SIGNIFICANCE: The ESRRB/SMAD7/MYC-positive feedback loop inhibits TGFß signaling to activate cell-cycle progression and promote proliferation in cervical cancer, thereby driving tumor growth.

Systematic review of subsequent pregnancy outcomes in couples with parental abnormal chromosomal karyotypes and recurrent pregnancy loss.

OBJECTIVE: To evaluate the current evidence of pregnancy outcomes among couples with recurrent pregnancy loss (RPL) with abnormal karyotypes vs. those with normal karyotypes and among couples with RPL and abnormal karyotypes after receiving expectant management vs. preimplantation genetic diagnosis (PGD). DESIGN: Systematic review and meta-analysis. SETTING: Academic medical centers. PATIENT(S): Pregnancy outcomes in 6,301 couples with RPL who conceived without medical intervention in 11 studies were analyzed. However, only 2 studies addressed the outcomes of couples with RPL and abnormal karyotypes after expectant management (75 cases) vs. PGD (50 cases). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The pregnancy outcomes in couples with RPL with abnormal and normal karyotypes across included studies were evaluated. RESULT(S): Compared with those with a normal karyotype, a significantly lower first pregnancy live birth rate (LBR) was found in couples with RPL with abnormal karyotypes (58.5% vs. 71.9%; odds ratio [OR], 0.55; 95% confidence interval [CI], 0.46-0.65; I2 =27%). A markedly decreased first pregnancy LBR was found in couples with a translocation (52.9% vs. 72.4%; OR, 0.44; 95% CI, 0.31-0.61; I2 =33%) but not in couples with an inversion. However, the differences in accumulated LBR (81.4% vs. 74.8%; OR, 0.96; 95% CI, 0.90-1.03; I2 = 0) were nonsignificant, whereas the miscarriage rate was distinctly higher in couples with RPL and abnormal karyotypes (53.0% vs. 34.7%; OR, 2.21; 95% CI, 1.69-2.89; I2 = 0). Compared with those who chose expectant management, differences in accumulated LBR were nonsignificant (60% vs. 68%; OR, 0.55; 95% CI, 0.11-2.62; I2 =71%), whereas the miscarriage rate (24% vs. 65.3%; OR, 0.15; 95% CI, 0.04-0.51; I2 = 45) was markedly low in couples with RPL and abnormal karyotypes who chose PGD. CONCLUSION(S): Couples with RPL and abnormal karyotypes had a higher miscarriage rate than couples with normal karyotypes but achieved a noninferior accumulated LBR through multiple conception attempts. In couples with RPL and abnormal karyotypes, PGD treatment did not increase the accumulated LBR but markedly reduced miscarriage rate compared with expectant management.