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

• Published in: BMC cancer 2019-10, Vol.19 (1), p.953-953, Article 953
• Main Authors: Chan, Ka-Kui, Wong, Esther Shuk-Ying, Wong, Ivy Tsz-Lo, Cheung, Claire Ling-Yang, Wong, Oscar Gee-Wan, Ngan, Hextan Yuen-Sheung, Cheung, Annie Nga-Yin
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Ankyrins; Apoptosis; Autophagy; Autophagy (Cytology); Autophagy-Related Protein 5 - metabolism; Cancer; Care and treatment; Cell Line, Tumor; Cell lines; Chemotherapy; Choriocarcinoma; Choriocarcinoma - metabolism; Choriocarcinoma - pathology; Cloning; Diagnosis; Disease; Female; Follow-Up Studies; Gene expression; Gene Knockdown Techniques; Hospitals; Humans; Hydatidiform mole; Hydatidiform Mole - metabolism; Hydatidiform Mole - pathology; Immunohistochemistry; Intracellular Signaling Peptides and Proteins - classification; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Malignancy; Microtubule-Associated Proteins - metabolism; Middle Aged; Oxidative Stress; p53 Protein; Pathology; Patient outcomes; Phagocytosis; Placenta; Placenta - cytology; Placenta - metabolism; Pregnancy; Proline; Proteins; Repressor Proteins - classification; Repressor Proteins - genetics; Repressor Proteins - metabolism; Senescence; siRNA; Transfection; Trophoblastic disease; Trophoblasts; Tumor proteins; Tumor Suppressor Protein p53 - metabolism; Young Adult
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-019-6206-z

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. 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. 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. iASPP regulates growth and the cellular responses towards oxidative stress in choriocarcinoma cells. Its overexpression is advantageous to the pathogenesis of GTD. (266 words).