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SIAH2 is specifically expressed during cervical carcinogenesis, and closely relates to the abnormal proliferation of
Li-Ping Jing1, Meng Li2, Xi-Yan Xia3
1Clinical Laboratory Department, Liaoning Cancer Hospital & Institute, 110042, Shenyang, Liaoning, China.
Background:
Cervical cancer is one of the most common malignancies in women worldwide. As a RING type ubiquitin ligase, SIAH2 has been reported to promote the progression of a variety of tumors by interacting with and targeting multiple chaperones and substrates. The aim of this study was to further identify the role and the related molecular mechanisms involved of SIAH2 in cervical carcinogenesis.
Methods And Results:
Cellular assays in vitro showed that knockdown of SIAH2 inhibited the proliferation, migration and invasion of human cervical cancer cells C33A and SiHa, induced apoptosis, and increased the sensitivity to cisplatin treatment. Knockdown of SIAH2 also inhibited the epithelial-mesenchymal transition and activation of the Akt/mTOR signaling pathway in cervical cancer cells, which were detected by Western blot. Mechanistically, SIAH2, as a ubiquitin ligase, induced the ubiquitination degradation of GSK3β degradation by using coIP. The results of complementation experiments further demonstrated that GSK3β overexpression rescued the increase of cell proliferation and invasion caused by SIAH2 overexpression. Specific expression of SIAH2 appeared in precancerous and cervical cancer tissues compared to inflammatory cervical lesions tissues using immunohistochemical staining. The more SIAH2 was expressed as the degree of cancer progressed. SIAH2 was significantly highly expressed in cervical cancer tissues (44/55, 80 %) compared with precancerous tissues (18/69, 26.1 %). Moreover, the expression level of SIAH2 in cervical cancer tissues was significantly correlated with the degree of cancer differentiation, and cervical cancer tissues with higher SIAH2 expression levels were less differentiated.
Conclusion:
Targeting SIAH2 may be beneficial to the treatment of cervical cancer.
Insights
The E3 ubiquitin ligase SIAH2 promotes cervical cancer progression by degrading GSK3β, inhibiting apoptosis, and driving epithelial-mesenchymal transition. Targeting SIAH2 offers a potential therapeutic strategy for cervical cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cervical cancer is a prevalent global malignancy in women.
- SIAH2 (Seven in Absentia Homolog 2), a RING-type ubiquitin ligase, is implicated in the progression of various cancers.
- The specific role and molecular mechanisms of SIAH2 in cervical carcinogenesis require further elucidation.
Purpose of the Study:
- To investigate the role of SIAH2 in cervical cancer.
- To identify the molecular mechanisms by which SIAH2 influences cervical carcinogenesis.
- To evaluate SIAH2 as a potential therapeutic target in cervical cancer.
Main Methods:
- In vitro cellular assays (proliferation, migration, invasion, apoptosis, chemosensitivity) in human cervical cancer cell lines (C33A, SiHa).
- Western blot analysis to assess epithelial-mesenchymal transition and Akt/mTOR signaling pathway activation.
- Co-immunoprecipitation (CoIP) to determine SIAH2's role in GSK3β ubiquitination and degradation.
- Immunohistochemical staining of cervical tissues to analyze SIAH2 expression in relation to disease progression and differentiation.
Main Results:
- SIAH2 knockdown inhibited cervical cancer cell proliferation, migration, invasion, and epithelial-mesenchymal transition, while inducing apoptosis and enhancing cisplatin sensitivity.
- SIAH2 knockdown suppressed Akt/mTOR pathway activation.
- SIAH2 promoted cervical cancer progression by inducing GSK3β ubiquitination and degradation.
- SIAH2 expression was significantly elevated in cervical cancer tissues compared to precancerous lesions and correlated with poor differentiation, indicating its role in advanced disease.
Conclusions:
- SIAH2 plays a crucial role in promoting cervical carcinogenesis through GSK3β degradation and influencing key signaling pathways.
- Elevated SIAH2 expression is a biomarker for advanced cervical cancer and poor differentiation.
- Targeting SIAH2 presents a promising therapeutic avenue for cervical cancer treatment.
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