A long noncoding RNA (lncRNA), the RNA component of mitochondrial RNA-processing endoribonuclease (RMRP), was shown to promote the growth and proliferation of colorectal cancer (CRC) cells by inhibiting activity of the tumor suppressor protein p53 in a Chinese study led by oncologists Fudan University Shanghai Cancer Center (FUSCC).

The study also demonstrated that RMPR expression was induced by the anticancer drugs, poly(ADP ribose) polymerase (PARP) inhibitors, and that targeting RMRP significantly enhanced the sensitivity of CRC cells to PARP inhibition.

"Our study is the first to elicit the role played by RMPR in CRC cells and demonstrate that targeting RMPR enhances the sensitivity of these cancer cells to PARP inhibition," study co-leader Xiang Zhou, an associate professor at FUSCC and the Institutes of Biomedical Sciences (IBS) at Fudan University, told BioWorld Science.

CRC is the third most common cancer worldwide, with an estimated 1.8 million new cases occurring worldwide in 2018, and is the fourth leading cause of mortality. Although mortality has been reduced by screening and improved treatments, new therapies are needed for advanced metastatic disease.

There is increasing evidence suggesting that PARP inhibitors may have an antitumor effect in subsets of CRC cells.

The tumor suppressor p53 is known to maintain genomic stability and prevent tumorigenesis, while p53 inactivation promotes cancer formation and induces drug resistance.

Various stress signals can activate p53, leading to induction of multiple genes involved in tumor suppression. Due to its cytotoxicity, p53 activity is usually restricted via multiple mechanisms under physiological conditions and in cancer.

The ubiquitin ligase MDM2, encoded by the p53-responsive MDM2 gene, is the main antagonist of p53 by promoting its ubiquitination and degradation.

Recently, lncRNAs have been increasingly implicated in regulating multiple cancer properties, including genomic instability, cell growth and immortality, angiogenesis, metastasis, and chemoresistance, while also having been shown to participate in the p53 network.

In their new study reported in the July 20, 2021, edition of Proceedings of the National Academy of Sciences, and appearing earlier online, researchers co-led by Zhou and Qian Hao, an assistant professor at FUSCC, found that RMRP was overexpressed and associated with a poor prognosis in CRC.

Specifically, they showed that ectopic RMRP suppressed p53 activity by promoting MDM2-induced p53 ubiquitination and degradation, while its depletion activated the p53 pathway.

"We transfected the RMRP-encoding plasmids as ectopic RMRP into HCT 116 cells and demonstrated that the expression of p53 and its target genes was significantly down-regulated," Zhou said.

He explained that HCT116 is a cell line commonly used in CRC research and that "RMRP depletion was achieved through [short interference] siRNA or CRISPR-Cas9 gene editing." RMRP was then shown to promote CRC growth and proliferation in a p53-dependent manner both in vitro and in vivo, with RMRP's anti-53 activity being achieved via its partner, small nuclear ribonucleoprotein A (SNRPA1).

"Ectopic RMRP significantly and dramatically promoted HCT116, but not HCT116p53-/- colorectal cell proliferation, with nude mice inoculated with HCT116 or HCT116p53-/- cells being used to demonstrate p53 dependency," said Zhou.

"These results suggest RMRP is a potential target in wild-type (WT) p53-harboring CRC," he said.

RMRP was further demonstrated to interact with SNRPA1 and sequester it in the nucleus, blocking its lysosomal proteolysis via autophagy.

Nuclear SNRPA1 was then shown to interact with p53 and enhance MDM2-induced proteasomal p53 degradation, while SNRPA1 ablation completely abrogated RMRP regulation of p53 and tumor cell growth, suggesting SNRPA1's key role in RMPR's anti-p53 function.

"Ablation of SNRPA1 mediated via siRNA significantly induced p53 activity and suppressed CRC cell growth," noted Zhou.

"In SNRPA1-knockdown CRC cells, ectopic RMRP failed to inhibit expression of p53 and its target gene p21, while [genetic] knockdown of SNRPA1 completely restored RMRP-induced CRC cell growth," he said.

PARP inhibitors were shown to induce RMRP expression via the transcription factor, CCAAT enhancer binding protein beta (C/EBPbeta), while RMRP conferred tumor resistance to PARP inhibition by preventing p53 activation.

Together, these findings show that in CRC, RMRP is oncogenic by inactivating p53 via SNRPA1, that targeting RMRP enhances sensitivity of CRC cells to PARP inhibition by reactivating p53, and may explain PAPR inhibitor resistance.

On the implications of these findings for the future management of CRC, "both RMRP and SNRPA1 might be ideal targets in combination with chemotherapy and PARP inhibitors in the treatment of WT p53-harboring CRC," said Zhou.

"Additionally, SNRPA1 was recently found to promote cassette exon inclusion and cancer metastasis, could be a pluripotent target," he noted, adding, "I believe exosome-delivered siRNA targeting RMRP or SNRPA1 might be a promising strategy for future clinical application."

Moreover, "more than 50% of CRCs sustain p53 mutations, significantly affecting cancer progression and treatment. We are therefore interested in exploring novel biomarkers or targets within the context of differential p53 status, which will be important in the development of targeted therapies."