A novel homeostatic loop of sorcin drives paclitaxel-resistance and malignant progression via Smad4/ZEB1/miR-142-5p in human ovarian cancer

Abstract

The primary chemotherapy of ovarian cancer (OC) often acquires chemoresistance. Sorcin (SRI), a soluble resistance-related calcium-binding protein, has been reported to be an oncogenic protein in cancer. However, the molecular mechanisms of SRI regulation and the role and aberrant expression of SRI in chemoresistant OC remain unclear. Here, we identified SRI as a key driver of paclitaxel (PTX)-resistance and explored its regulatory mechanism. Using transcriptome profiles, qRT-PCR, proteomics, Western blot, immunohistochemistry, and bioinformatics analyses, we found that SRI was overexpressed in PTX-resistant OC cells and the overexpression of SRI was related to the poor prognosis of patients. SRI was a key molecule required for growth, migration, and PTX-resistance in vitro and in vivo and was involved in epithelial–mesenchymal transition (EMT) and stemness. Mechanistic studies showed that miR-142-5p directly bound to the 3ʹ-UTR of SRI to suppress its expression, whereas a transcription factor zinc-finger E-box binding homeobox 1 (ZEB1) inhibited the transcription of miR-142-5p by directly binding to the E-box fragment in the miR-142 promoter region. Furthermore, ZEB1 was negatively regulated by SRI which physically interacted with Smad4 to block its translocation from the cytosol to the nucleus. Taken together, our findings unveil a novel homeostatic loop of SRI that drives the PTX-resistance and malignant progression via Smad4/ZEB1/miR-142-5p in human OC. Targeting this SRI/Smad4/ZEB1/miR-142-5p loop may reverse the PTX-resistance.

Clinical Significance and Prognostic Value of Human Soluble Resistance-Related Calcium-Binding Protein: A Pan-Cancer Analysis

“…Our previous work revealed that SRI promoted the stemness and EMT process in ovarian cancer ( 35 ), we, therefore, wanted to investigate the association of SRI expression with stemness score and EMT-related genes in cancers. First, the sorcin expression was upregulated in the OVCAR-3 and SKOV-3 spheres cells compared with the respective adherent cells ( Supplementary Figure 5 ).…”

“…Genomic amplification of SRI has long been recognized as an occasional event of such genomic co-amplification ( 52 ). However, accumulating evidence indicated that the pathways involved in the tumor malignant behaviors, such as TGF-β and JAK-STAT3 signaling were affected by the SRI gene amplification ( 35 , 53 ). In addition, we found co-occurrence of ADAM22, DBF4, ABCB1, ABCB4, and RUNDC3B alterations was observed with the SRI alterations, which was consistent with the previous reports ( 48 ).…”

“…Our previous findings revealed that SRI promoted the paclitaxel resistance and malignant progression in ovarian cancer ( 23 ). Thus, here we postulated that SRI might function as a critical oncogenic, resistant effector in pan-cancer, and played crucial roles in cancer immunity.…”

Bevacizumab confers significant improvements in survival for ovarian cancer patients with low miR-25 expression and high miR-142 expression

“…In contrast, miR-142 promoted organoid formation by breast cancer stem cells (BCSCs) and enhanced tumor growth initiated by human BCSCs in vivo [ 14 ]. In ovarian cancer, miR-142-5p significantly decreased cell proliferation, arrested the cell cycle at the S phase, reduced the ability of colony formation, inhibited cell migration and invasion, and enhances cisplatin-induced apoptosis [ 15 , 16 ]. Zhang et al showed that low miR-142 expression was associated with a worse survival [ 15 ].…”

“…In ovarian cancer, miR-142-5p significantly decreased cell proliferation, arrested the cell cycle at the S phase, reduced the ability of colony formation, inhibited cell migration and invasion, and enhances cisplatin-induced apoptosis [ 15 , 16 ]. Zhang et al showed that low miR-142 expression was associated with a worse survival [ 15 ]. In contrast, our study revealed that low miR-142 expression seemed to be correlated with a better survival.…”