Distinct expression and prognostic values of the replication protein A family in gastric cancer

Abstract

The replication protein A (RPA)1-4 family are single-stranded DNA-binding proteins that are essential components of DNA replication, repair and recombination, and cell cycle regulation. The present study aimed to evaluate the prognostic value of the RPA family members in patients with gastric cancer (GC), using datasets retrieved from the Oncomine public database. Datasets were retrieved for the purpose of comparing the RPA expression levels between GC and normal tissues. Additionally, Kaplan-Meier analysis was used to compare the overall survival (OS) times of GC patients that expressed different levels of RPA proteins. RPA1, 2, and 3 expression levels were all significantly upregulated in gastric intestinal-type, diffuse gastric, and gastric mixed adenocarcinomas, compared with those in normal mucosal tissues. Moreover, high mRNA expression levels of RPA3 and 4 predicted poorer OS times in all GCs, as well as patients with human epidermal growth factor receptor 2-negative and -positive GC. The high-risk group, separated by RPA signature, showed a poorer outcome than the low-risk group. RPA3 was the most strongly correlated with CD4+ T-cell levels. In conclusion, RPAs are novel prognostic indicators in GC, and can also predict the features of immunological diseases. Future experimental investigation into the roles of RPAs concerning the pathogenesis and development of GC may provide a novel biomarker or therapeutic target, improving the prognosis of patients with GC.Abbreviations: RPA, replication protein A; KM, Kaplan-Meier; OS, overall survival; HER2, human epidermal growth factor receptor 2; TIMER, tumor immune estimation response

Replication protein A: a multifunctional protein with roles in DNA replication, repair and beyond

“…Overexpressed RPA1 and/or RPA2 are detected in various cancers, suggesting that RPA may be useful as a prognostic marker in cancer patients ( 322–330 ). Elevated RPA3 expression is also implicated in the development of gastric ( 330 , 331 ) and hepatocellular carcinoma ( 332 ). The oncogenic properties of RPA appear linked to the cyclin D pathway ( 322 , 325 , 329 ), which drives the G1/S-phase transition.…”

Antagonistic roles of canonical and alternative RPA in tandem CAG repeat diseases

“…Increased and decreased levels of RP2 and RPA4, respectively, have been observed in many cancers, supporting Alt-RPA↔RPA antagonistic roles in chromosomal replication and proliferation 47,136 . Humans inheriting Xq21.33 duplications encompassing only the RPA4 and DIAPH2 genes are phenotypically normal (males and females), suggesting that Alt-RPA dosage variations may not be pathogenic 137 .…”

“…Humans inheriting Xq21.33 duplications encompassing only the RPA4 and DIAPH2 genes are phenotypically normal (males and females), suggesting that Alt-RPA dosage variations may not be pathogenic 137 . However, somatically elevated RPA4 levels are associated with better prognosis in gastric cancers, suggesting that RPA4 levels can be important in disease states 136 . It is tempting to speculate that an antagonistic role of Alt-RPA upon DNA replication/proliferation may be linked to the reduced cancer incidence in HD patients [138][139][140][141][142] .…”

Actin nucleation safeguards single-stranded DNA and promotes replication fork protection

“…To efficiently support these processes, cells maintain a high level of RPA in the nucleus throughout the S-phase (around 8fold excess of what is required to support unperturbed replication 10 ). However, increased RPA levels can be toxic and drive genome instability and cancer progression, likely due to excessive formation of RPA-ssDNA complexes 10,14,[41][42][43] . Nonetheless, the prevailing view in the field is that the RPA molecules are freely diffused throughout the nucleus and bind rapidly to available ssDNA by a passive mechanism.…”