Function of B-cell lymphoma 6 in trophoblast cells

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B-cell lymphoma 6 promotes proliferation and survival of trophoblastic cells

Preeclampsia is one of the leading causes of maternal and perinatal mortality and morbidity worldwide. Preeclampsia originates in the placenta and several studies demonstrated that many signaling pathways are affected in preeclamptic placentas.^1,2

B-cell lymphoma 6 (BCL6) is a key oncogene in B-cell lymphomagenesis.³ The gene expression of BCL6 is also repeatedly reported to be increased in the placenta of patients with early as well as with late preeclampsia. The protein level of BCL6 is elevated in preeclamptic placentas and elevated BCL6 is well correlated with the hallmark of preeclampsia.⁴ Since BCL2 targets a large range of the genes that are associated with various cellular functions, including differentiation, survival, DNA damage response, and cell-cycle regulation, it should be tempting to discovery the involvement of BCL6 in the pathogenesis of preeclampsia.

In a recent paper published in Cell Cycle, Muschol-Steinmetz C, et al⁵ made one very intriguing observation that BCL6 is present in all 3 studied trophoblast cell lines, but it is predominantly expressed in trophoblastic HTR-8/SVneo cells derived from a 1^st trimester placenta compared to the malignant BeWo and JAR cells which are less dependent on BCL6. It indicates that BCL6 might be involved in the trophoblast expansion in the early stage of placental development. The authors then focused on the function of BCL6 in the cell cycle and cell survival of trophoblasts. By using of siRNA or small molecule inhibitor specifically targeting BCL6, they demonstrated that BCL6 is required for the proliferation of trophoblasts and that its depletion results in apoptosis. In HTR cells with BCL6 depletion, a small but distinctive G2/M peak was observed. The mitotic arrest is associated with shortened sister centromere distance and fragmented/clustered centrosomes in trophoblasts, suggesting that BCL6 could be involved in mitotic progression by interfering with microtubule-kinetochore attachment and centrosome integrity. This is the first piece of evidence to demonstrate that properly regulated BCL6 is important for a smooth mitotic progression of trophoblasts.

As the preeclamptic placenta is characterized by hypoxia and ischemia releasing a variety of stress mediators including reactive oxygen species (ROS) such as hydrogen peroxide,⁶ the expression pattern of BCL6 under low concentration of oxygen and other cellular stress was examined. In Muschol-Steinmetz C et al's report, the authors showed that BCL6 is stabilized and promotes survival of trophoblasts either under hypoxic situation or under the H₂O₂ treatment, especially HTR cells, the 1^st trimester trophoblastic cells. In contrast, depletion of BCL6 induced apoptosis under stress situation.

Taken together with previous observations, the result of Muschol-Steinmetz C, et al. shed new light on the function of BCL6 in trophoblast cells: BCL6 is required for proliferation and protects cells from apoptotic induction, leading to trophoblast cells survival under the stress environment in the placenta. These findings have important implications for the pathogenesis of Preeclampsia.