Chinese Medical Journal study uncovers the role of non-coding RNA in pancreatic cancer

Pancreatic cancer, one of the leading causes of deaths, refers to the abnormal growth of cells in the pancreas. Only 10% of patients live more than five years after the onset of this vicious malignancy. One reason for such high lethality is the anatomical location of the pancreas. It is located deep in the viscera, which prevents early detection of tumors and allows the cancer to metastasize into other vital organs. This delayed diagnosis results in identifying a lower number of patients (around 10–15%) eligible for surgical resection. Due to high recurrence rates, the five- year survival rate remains as low as 15–20%, even after resection. Moreover, pancreatic cancer can easily acquire drug resistance, reducing the efficacy of chemotherapy.

Against this backdrop, there is a dire need to find new therapeutic avenues. Pancreatic cancer is largely driven by key genes like KRAS, TP53, CDKN2A, and SMAD4. Understanding the molecular mechanisms by which these genes promote the cancer and the RNA machinery that regulates these genes could be a viable avenue for future treatments.

A growing body of research has highlighted the role of noncoding RNAs (ncRNAs) in pancreatic cancer. Unlike messenger RNAs (mRNAs), ncRNAs do not code for proteins; instead, they are involved in gene regulation and RNA processing. ncRNA is a broad category that includes various types of non-protein coding RNA, such as microRNAs (miRNAs), circular RNAs (circRNAs), long ncRNAs (lncRNAs), tRNA-derived small RNAs (tsRNA), PIWI-interacting RNAs (piRNA), and small nucleolar RNAs (snoRNA). Previous studies have shown that all these types of ncRNAs are dysregulated in pancreatic cancer. However, while individual ncRNAs have been studied in this context, the findings have not been compiled together.

Now, scientists from West China Hospital, Sichuan University, China, have explored how different ncRNAs are dysregulated in pancreatic cancer. The research team was led by Mr. Xiaojuan Yang and their study was published in the Chinese Medical Journal and made available online on April 10, 2025, and was published in Volume 138, Issue 9 on May 05, 2025.

The first question tackled in the study is how ncRNAs are dysregulated. Chromosomal defects, such as amplifications, deletions, and mutations in regions that code for ncRNAs, are frequently found in pancreatic cancer. This implies that ncRNA dysregulation begins with chromosomal defects. Dysregulation of transcription factors (proteins that control gene expression) associated with ncRNAs can also lead to aberrant ncRNA expression. Additionally, aberrant epigenetic regulation of genes coding for ncRNAs can contribute to this dysregulation. Aberrant DNA methylation (addition of methyl groups to DNA) can suppress ncRNA expression, while histone modification can lead to overexpression or suppression of ncRNA coding genes. Finally, the disruption of RNA splicing proteins involved in ncRNA biogenesis can dysregulate ncRNA and have been shown to promote treatment resistance in pancreatic cancer.

So, how do ncRNAs promote pancreatic cancer? ncRNA-protein interactions play a key part in this process and can happen in three ways. Firstly, ncRNA can act as scaffolding for multiple proteins, facilitating the assembly of cancer-promoting protein complexes.

“ncRNAs have the capacity to interact with one or more protein molecules, thereby facilitating and stabilizing their molecular interactions,” explains Mr. Yang. “In such scenarios, protein A may undergo specific posttranslational modifications mediated by the catalytic activity of protein B. Alternatively, protein A may be transactivated by the regulatory function of protein B.”

For example, in the pancreas, lncRNA MTSS1-AS binds to the transcription factor MZF1, enhancing the interaction between MZF1 and the E3 ubiquitin ligase STUB1. This leads to the degradation of MZF1 and the upregulation of the tumor suppressor gene MTSS1. This is hampered in pancreatic cancer. ncRNA scaffolds can also enhance interactions between proteins and RNA or DNA.

Secondly, ncRNAs can act as ‘protein sponges,’ sequestering proteins and tethering themselves to prevent protein-protein/RNA/DNA interactions. For instance, in the pancreas, circRTN4 interacts with the epithelial-to-mesenchymal transition-driver RAB11FIP1 to block its degradation. Thirdly, ncRNAs can bind with proteins to translocate or redistribute them to specific subcellular compartments. ncRNAs can also promote cancer stemness, allowing the self-renewal of cancer cells. Furthermore, ncRNA-protein interactions can mediate metabolic reprogramming, which supports the uncontrolled proliferation of cancer cells.

This study highlights that ncRNAs can act as both biomarkers and potential therapeutic targets in pancreatic cancer. “The involvement of aberrant ncRNA expression in cellular biological processes associated with pancreatic cancer suggests that targeting these ncRNAs could offer therapeutic potential,” notes Mr. Yang. The researchers also mention that utilizing ncRNAs as diagnostic markers warrants further investigation based on clinical trials.

Let us hope further research efforts pave the way to a future of creating a cancer-free society!

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Reference

DOI: 10.1097/CM9.0000000000003587