Overexpression of iASPP is required for autophagy in response to oxidative stress in choriocarcinoma

Abstract

Background Gestational trophoblastic disease (GTD) is a heterogeneous group of diseases developed from trophoblasts. ASPP (Ankyrin-repeat, SH3-domain and proline-rich region containing protein) family proteins, ASPP1 and ASPP2, have been reported to be dysregulated in GTD. They modulate p53 activities and are responsible for multiple cellular processes. Nevertheless, the functional role of the ASPP family inhibitory member, iASPP, is not well characterized in GTD. Methods To study the functional role of iASPP in GTD, trophoblastic tissues from normal placentas, hydatidiform mole (HM) and choriocarcinoma were used for immunohistochemistry, whereas siRNAs were used to manipulate iASPP expression in choriocarcinoma cell lines and study the subsequent molecular changes. Results We demonstrated that iASPP was overexpressed in both HM and choriocarcinoma when compared to normal placenta. Progressive increase in iASPP expression from HM to choriocarcinoma suggests that iASPP may be related to the development of trophoblastic malignancy. High iASPP expression in HM was also significantly associated with a high expression of autophagy-related protein LC3. Interestingly, iASPP silencing retarded the growth of choriocarcinoma through senescence instead of induction of apoptosis. LC3 expression decreased once iASPP was knocked down, suggesting a downregulation on autophagy. This may be due to iASPP downregulation rendered decrease in Atg5 expression and concomitantly hindered autophagy in choriocarcinoma cells. Autophagy inhibition per se had no effect on the growth of choriocarcinoma cells but increased the susceptibility of choriocarcinoma cells to oxidative stress, implying a protective role of iASPP against oxidative stress through autophagy in choriocarcinoma. Conclusions iASPP regulates growth and the cellular responses towards oxidative stress in choriocarcinoma cells. Its overexpression is advantageous to the pathogenesis of GTD. (266 words).

ATF3 drives senescence by reconstructing accessible chromatin profiles

“…3A). Among them, FOXA1, PLAT, CD44, FGF5, DIO2 and other genes are upregulated, whereas PLCB1, SETBP1, EHD3, ZNF423, PHGDH and other genes are downregulated in multiple senescence systems(Chan et al, 2019; Cho et al, 2019; Galanos et al, 2016; Hari et al, 2019; Hernandez-Segura et al, 2017; Komseli et al, 2018; Lau, Porciuncula, Yu, Iwakura, & David, 2019; Leveque et al, 2019; Q. Li et al, 2013; Limbad et al, 2020; Lowe & Raj, 2014; Nagano et al, 2016; Pan et al, 2019; Pantazi et al, 2019; Suwan et al, 2009; Wu, Pepowski, Takahashi, & Kron, 2019; Zhou et al, 2010), as are consistent with our results.…”

iASPP suppresses Gp78-mediated TMCO1 degradation to maintain Ca 2+ homeostasis and control tumor growth and drug resistance

“…S3 B ). This attracted our attention because iASPP has been shown to be overexpressed in multiple cancers, including COAD ( 35 , 40 – 42 ), and our data also revealed that iASPP was increased in colon cancer tissues compared with matched adjacent normal controls ( Fig. 3 E ).…”

Discovery of the prognostic marker in the whole blood sample of gestational trophoblastic neoplasia beyond immunohistochemical tissue markers: mdm2

“…Downregulation of a member of apoptosis-stimulating proteins of p53 (ASPPs), ASPP1 was demonstrated in GTD and lower ASPP1 was also shown in progression to GTN which may explain the pathogenesis through decreased apoptosis [23]. Another study revealed the overexpression of ASPP family inhibitory member iASPP, with a progressive increase from hydatidiform mole to choriocarcinoma [24]. Another study showed that a molecule DJ-1 as a regulator of Phosphatase and TENsin homolog deleted on chromosome 10 (PTEN), which is a frequently mutated tumor suppressor gene in carcinogenesis may play a role in apoptotic activity regulation of GTD in relation to PTEN and p53 [25].…”