Abstract
Worldwide, the number of cancer-related deaths continues to increase due to the ability of cancer cells to become chemotherapy-resistant and metastasize. For women with ovarian cancer, a staggering 70% will become resistant to the front-line therapy, cisplatin. Although many mechanisms of cisplatin resistance have been proposed, the key mechanisms of such resistance remain elusive. The RNA binding protein with multiple splicing (RBPMS) binds to nascent RNA transcripts and regulates splicing, transport, localization, and stability. Evidence indicates that RBPMS also binds to protein members of the AP-1 transcription factor complex repressing its activity. Until now, little has been known about the biological function of RBPMS in ovarian cancer. Accordingly, we interrogated available Internet databases and found that ovarian cancer patients with high RBPMS levels live longer compared to patients with low RBPMS levels. Similarly, immunohistochemical (IHC) analysis in a tissue array of ovarian cancer patient samples showed that serous ovarian cancer tissues showed weaker RBPMS staining when compared with normal ovarian tissues. We generated clustered regularly interspaced short palindromic repeats (CRISPR)-mediated RBPMS knockout vectors that were stably transfected in the high-grade serous ovarian cancer cell line, OVCAR3. The knockout of RBPMS in these cells was confirmed via bioinformatics analysis, real-time PCR, and Western blot analysis. We found that the RBPMS knockout clones grew faster and had increased invasiveness than the control CRISPR clones. RBPMS knockout also reduced the sensitivity of the OVCAR3 cells to cisplatin treatment. Moreover, β-galactosidase (β-Gal) measurements showed that RBPMS knockdown induced senescence in ovarian cancer cells. We performed RNAseq in the RBPMS knockout clones and identified several downstream-RBPMS transcripts, including non-coding RNAs (ncRNAs) and protein-coding genes associated with alteration of the tumor microenvironment as well as those with oncogenic or tumor suppressor capabilities. Moreover, proteomic studies confirmed that RBPMS regulates the expression of proteins involved in cell detoxification, RNA processing, and cytoskeleton network and cell integrity. Interrogation of the Kaplan–Meier (KM) plotter database identified multiple downstream-RBPMS effectors that could be used as prognostic and response-to-therapy biomarkers in ovarian cancer. These studies suggest that RBPMS acts as a tumor suppressor gene and that lower levels of RBPMS promote the cisplatin resistance of ovarian cancer cells.
Highlights
Ovarian cancer remains the most lethal gynecological malignancy in the UnitedStates [1,2]
Our findings provide new evidence indicating that reduced levels of RNA binding protein with multiple splicing (RBPMS) contribute to the cell growth and invasion as well as drug resistance of ovarian cancer cells as well as that RBPMS could act as a tumor suppressor gene in these cells
As we observed that RBPMS was reduced at the RNA and protein levels in serous ovarian cancer patients when compared with normal ovaries, we investigated the RBPMS
Summary
Ovarian cancer remains the most lethal gynecological malignancy in the UnitedStates [1,2]. Ovarian cancer remains the most lethal gynecological malignancy in the United. The American Cancer Society estimates about 21,410 new cases of ovarian cancer will be diagnosed in the United State in 2021, of which 13,770 (>60%) patients will die of the disease [2]. This high death rate stems from most ovarian cancer patients not being diagnosed until an advanced stage. 90% of ovarian cancers are malignant epithelial ovarian cancers (EOCs) [3]. EOC is a heterogeneous disease comprised of five histological subtypes: high-grade serous, low-grade serous, mucinous, endometrioid, and clear cell tumors [4]. Most ovarian cancer patients respond to standard treatment, which is based on a combination of cytoreductive surgery and platinum/taxane chemotherapy, relapse occurs in over 60% of treated patients, resulting in chemoresistant fatal disease [7]
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