Glaucocalyxin A Inhibits the Malignant Progression of Epithelial Ovarian Cancer by Affecting the MicroRNA-374b-5p/HMGB3/Wnt-β-Catenin Pathway Axis

Chen, Feng; Sun, Fuchun; Liu, Xia; Shao, Jun; Zhang, Bei

doi:10.3389/fonc.2022.955830

Cited by 1 publication

(1 citation statement)

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“…The results demonstrated that the OS of the high ITIH3 protein expression level group was significantly higher than the low ITIH3 protein expression group. Furthermore, in a preliminary study (5,23), the association between ITIH3 protein expression levels and key Bcl-2 signaling pathway proteins, as well as the OS of patients with high and low protein expression levels of Bcl-2 in OC were assessed using The Cancer Genome Atlas database (24). The results demonstrated that the protein expression levels of Bcl-2 were not significantly associated with to prognosis in OC tissues without chemotherapy (data not shown), therefore the Bcl-2 protein expression of TMAs was not assessed in the present study.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of ITIH3 contributes to cisplatin‑based chemotherapy resistance in ovarian carcinoma via the Bcl‑2 mediated anti‑apoptosis signaling pathway

et al. 2022

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Platinum resistance of ovarian cancer is one of the primary factors of poor prognosis and inter-α-trypsin inhibitor heavy chain 3 (ITIH3) is a potential DDP resistance-associated gene. The present study assessed protein expression levels of ITIH3 in human ovarian cancer and evaluated the relationship between its expression and platinum-resistance in patients. Furthermore, the effect of ITIH3 on cisplatin (DDP)-resistant ovarian cancer cells and the underlying molecular mechanism were evaluated. Tissue microarrays of ovarian cancer samples were used to assess the association between ITIH3 protein expression levels and drug resistance and the prognosis of ovarian cancer. ITIH3 RNA interference (RNAi) ovarian cancer cell lines were constructed and expression levels of anti-and pro-apoptotic proteins of the Bcl-2 associated pathway, including Bcl-2, Bcl-xL, Mcl-1, Bak, Bim, Bax, caspase 3 and poly ADP-ribose polymerase (PARP), were assessed following DDP treatment. The Bcl-2 inhibitor ABT-737 was used to rescue DDP-resistance induced by loss of ITIH3 in vitro. Finally, a subcutaneous xenograft tumor model was used to evaluate the effect of multiple DDP injections on expression levels of apoptosis-related proteins like Bcl-2, Bcl-xL, Bak, caspase 3 and PARP. The results of tissue microarray immunohistochemistry revealed that decreased ITIH3 protein expression levels were associated with a shorter overall survival for patients with ovarian cancer. The results of Cell Counting Kit-8 assay showed that the half-maximal inhibitory concentration and resistance index of DDP in SKOV3-ITIH3 and OVCAR3-ITIH3 RNAi cells were significantly higher than in control groups. Following DDP treatment, the results of western blotting revealed that expression levels of anti-apoptotic proteins of the Bcl-2 family significantly increased in SKOV3-ITIH3 and OVCAR3-ITIH3 RNAi cells. Pro-apoptotic protein expression was not significantly changed following DDP treatment, whereas cleaved caspase 3, caspase 3 and cleaved (C-PARP) were markedly downregulated. The Bcl-2 inhibitor ABT-737 was demonstrated to reverse increased DDP resistance induced by ITIH3 expression in flow cytometric and western blotting analysis. In the subcutaneous murine xenograft model, an increased number of DDP injections yielded a decrease in phosphorylated Bcl-2, cleaved caspase 3, caspase 3 and C-PARP protein expression levels in the SKOV3-ITIH3 RNAi group tested by western blotting. To the best of our knowledge, this is the first study to demonstrate that ITIH3 could be a vital molecule involved in chemosensitivity via regulation of the Bcl-2 family-mediated apoptotic pathway. Lower protein expression levels of ITIH3 were significantly associated with platinum resistance and poor prognosis in ovarian cancer. ITIH3 may predict cisplatin-resistance in ovarian cancer.

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Section: Discussionmentioning

confidence: 99%