High expression of RIPK2 is associated with Taxol resistance in serous ovarian cancer

Abstract

Background Taxol resistance in serous ovarian cancer is responsible for its poor prognosis, yet the underlying mechanism is still poorly understood. Thus, we probed the mechanism of Taxol resistance in serous ovarian cancer with multiple bioinformatic methods to provide novel insights into potential therapies. Methods The differentially expressed genes (DEGs) in Taxol-sensitive and Taxol-resistant cell lines and their relationship with the overall survival (OS) and progression-free interval (PFI) of ovarian cancer patients were analyzed using gene expression datasets from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The role of receptor interacting serine/threonine kinase 2 (RIPK2) was validated via identification of its coexpressed genes, functional analysis and generation of a protein-protein interaction (PPI) network. The single sample gene set enrichment analysis (ssGSEA) was used to explore immune infiltration, and genomic alterations of RIPK2 were also analyzed via cBio Cancer Genomics Portal (cBioProtal). Results RIPK2 was highly expressed in Taxol resistant ovarian cancer cell lines, and its high expression was also linked with shorter OS and PFI in serous ovarian cancer patients. The PPI network analysis and pathway analysis demonstrated that RIPK2 might participate in the positive regulation of NF-κB transcription factor activity. RIPK2 expression was related to tumor microenvironment alterations, which might participate in the formation of Taxol resistance. Conclusions Our studies suggested that high expression of RIPK2 is related to Taxol resistance in serous ovarian cancer, and that RIPK2 induces Taxol resistance through NOD1/RIPK2/NF-κB inflammatory pathway activation and tumor microenvironment changes.

NOD1 and NOD2 Are Potential Therapeutic Targets for Cancer Immunotherapy

“…Since HPV16-positive cervical cancer cells were more likely to undergo apoptosis when NOD1 was activated, this suggested that NOD1mediated apoptosis may help to prevent cervical cancer [34]. In contrast to Liu's result [34], NOD1 was shown to be significantly expressed in cervical squamous cell carcinoma (CSCC), and overexpression of NOD1 increased proliferation, invasion, and migration of CSCC cell lines by activating NF-κB and ERK signaling pathways and increasing IL-8 production [35][36][37].…”

“…Ovarian Cancer. According to Shen's research [36], serous ovarian cancer is resistant to taxol through the NOD1/RIPK2/NF-κB inflammatory pathway, and NOD1/ RIP2 promotes the growth of ovarian cancer by turning on NF-B signaling. However, they did not investigate if the effect is related to the microbiota in the ovary and the permeability of the ovarian wall, which might be disturbed by NOD1 expression [37].…”

“…However, the role of NOD1 and NOD2 in cancer is complicated, indicating that more studies in this field are necessary. It has been found that NOD1 activation contributes to tumor suppression mainly through RIP2/TAK1/ MAPK pathway-mediated apoptosis in oral cancer [45], thyroid cancer [23], breast cancer [26], and GC 27, whereas NOD1 overexpression is associated with tumor development with decreased chemotherapy sensitivity but enhanced immunosuppression in HNSCC 24, ESCC25, prostate cancer [33], and ovarian cancer [36]. Based on those studies, we examined the conflicting roles of NOD1 in HCC [28,29], CRC [22,[30][31][32], and cervical cancer [34,35] and found that NOD1-regulated apoptotic activation is a common feature in tumor suppression, whereas NOD1-mediated immunosuppression is another comparable characteristics in NOD1promoted malignancy which has been described by several studies [31,32].…”

RIPK2: a promising target for cancer treatment

“…However, paclitaxel resistance is one of the primary factors for the poor prognosis. In a bioinformatics study searching for potential biomarkers associated with paclitaxel resistance in OC treatment, researchers found a correlation between the higher expression of RIPK2 and the development of paclitaxel resistance ( Shen et al, 2022 ). The mechanism leading to the resistance, for one thing, depends on the over-activation of RIPK2-mediated NF-κB signaling pathway, and another facet is the change of tumor microenvironment caused by RIPK2-mediated immune infiltration, including CD4 + memory T-cell, dendritic cells (DCs), common lymphoid progenitors (CLPs) ( Shen et al, 2022 ; Zhang and Wang, 2022 ).…”

“…In a bioinformatics study searching for potential biomarkers associated with paclitaxel resistance in OC treatment, researchers found a correlation between the higher expression of RIPK2 and the development of paclitaxel resistance ( Shen et al, 2022 ). The mechanism leading to the resistance, for one thing, depends on the over-activation of RIPK2-mediated NF-κB signaling pathway, and another facet is the change of tumor microenvironment caused by RIPK2-mediated immune infiltration, including CD4 + memory T-cell, dendritic cells (DCs), common lymphoid progenitors (CLPs) ( Shen et al, 2022 ; Zhang and Wang, 2022 ). Therefore, this makes sense to choose RIPK2 as a candidate target for OC, as RIPK2 inhibitors could be used in combination with chemotherapy agents to grapple with potential drug resistance and significantly ameliorate the original immune microenvironment that promotes tumor progression.…”