A recent study published in the International Journal of Molecular Sciences evaluated genes with copy number (CN) alterations (CNAs) to identify biomarkers for ovarian cancer (OC) prognosis.

Study: AhRR and PPP1R3C: Potential Prognostic Biomarkers for Serous Ovarian Cancer. Image Credit: ESBProfessional/Shutterstock.com

Background

OC encompasses a set of heterogeneous neoplasms with distinct biological and morphological features. OC can be stratified into types I and II. Type I tumors include low-grade mucinous, serous, clear cell, and endometrioid carcinomas, whereas most type II tumors are high-grade serous carcinomas.

The standard treatment for OC is carboplatin or a combination of carboplatin and paclitaxel. Bevacizumab is a second-line maintenance treatment. Notwithstanding, the recurrence of OC post-first-line chemotherapy is consistently high. The lack of effective therapies contributes to the high mortality rate and poor prognoses in advanced OC patients.

The mechanisms underlying chemoresistance are poorly defined, albeit studies implicate cancer stem cells (CSCs) and various signaling pathways. Technological advances have led to the identification of novel biomarkers.

CNAs contribute to genomic heterogeneity; recently, CNA analysis has revealed genetic signatures predicting poor prognoses across cancer types.

The study and findings

In the present study, researchers evaluated genes involved in CN gains in OC cell lines and ovarian CSCs to identify potential prognostic biomarkers of serous OC. OC spheroids were derived from three cell lines (Ovcar5, Ovcar9, and Caov3).

Spheroids had higher expression of known OC stemness markers [aldehyde dehydrogenase 1 (ALDH1), cluster of differentiation 44 (CD44), Nanog homeobox (NANOG), and ATP-binding cassette superfamily G member 2 (ABCG2)].

Further, an array of comparative genomic hybridization analyses was performed to characterize spheroids and cell lines at the genomic level. The team explored the genes involved in CNAs and their corresponding pathways.

The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of Caov3 spheroids demonstrated CN gains in genes linked to chemical carcinogenesis.

Notably, the Caov3 cell line showed CN loss in genes associated with the forkhead box O (FoxO) signaling pathway. Ovcar8 spheroids exhibited CN gains in genes in angiogenesis, migration, survival, proliferation, and invasion pathways.

Ovcar5 spheroids showed lower functionality of those in the platinum drug resistance pathway, resulting in lower cell cycle regulation and pro-apoptotic effect, consistent with CSCs.

None of the spheroids shared genes with CN gains. Further, the team analyzed the correlation between the expression of select genes in OC prognosis and patients' survival.

This revealed a strong correlation of aryl hydrocarbon receptor repressor (AhRR), polypeptide-N-acetylgalactosaminyltransferase 10 (GALNT10), and protein phosphatase one regulatory subunit 3C (PPP1R3C) with OC prognosis.

Further investigations were focused on PPP1R3C and AhRR because the role of GALNT10 in OC has been previously described. To this end, the Cancer Genome Atlas (TCGA) data were analyzed. The correlation of both genes with the overall survival of patients was significant.

Moreover, the expression of PPP1R3C and AhRR correlated with CSC stemness markers. In addition, higher AhRR or PPP1R3C expression negatively correlated with progression-free survival of patients.

Real-time polymerase chain reaction (PCR) revealed a significant increase in the expression of AhRR in Ovcar5 and Ovcar8 cell lines and spheroids but not in Caov3. The expression of PPP1R3C was significantly elevated in only the Ovcar5 cell line and spheroids.

These findings point to the absence of a correlation between mRNA expression and CNAs of these genes. Besides, the presence of CNAs did not appear prognostic.

However, a few CSC sub-populations sustained elevated expression of PPP1R3C and AhRR. Finally, the researchers explored correlations between the expression of these two genes and poor outcomes in patients with other cancers.

As such, increased AhRR expression significantly correlated with worse overall patient survival in several cancers. On the other hand, the prognostic role of PPP1R3C varied by cancer type.

Conclusions

The study analyzed genes with CNAs in three OC cell lines and spheroids. The expression of three genes with CN gains negatively correlated with the overall survival of OC patients. AhRR or PPP1R3C expression positively correlated with the expression of CSC stemness markers.

However, no correlation was observed between CN gains of these genes and their expression in OC cell lines or spheroids. Nevertheless, further studies are required to characterize these genes' role in CSCs better.

Journal reference:

• Ardizzoia, A. et al. (2023) "AhRR and PPP1R3C: Potential Prognostic Biomarkers for Serous Ovarian Cancer", International Journal of Molecular Sciences, 24(14), p. 11455. doi: 10.3390/ijms241411455. https://www.mdpi.com/1422-0067/24/14/11455