One study was recently published in the journal Reports Medicine. Scientists conducted a comprehensive study to better understand the molecular mechanisms of pancreatic cancer and find new ways to improve the diagnosis and development of this extremely aggressive and difficult-to-** disease, the report said.
They analyzed transcriptome data from patients' tumor samples and identified two main molecular subtypes of pancreatic cancer – classical and basal-like. These subtypes differ significantly in terms of disease prognosis and response.
The classical subtype has a better prognosis and is more sensitive to chemotherapy. Conversely, basal-like is associated with poorer patient survival and resistance to anticancer drugs.
Further analysis showed that these isoforms have completely different alternative splicing signatures, which is one of the key processes that determine the diversity of proteins in cells. Splicing allows a gene to produce multiple protein isoforms that can perform different functions. Researchers have identified dozens of specific splice variants that differ in classical and basal-like tumors.
Importantly, many of these variants are closely related to patient survival, even within the same tumor subtype. For example, higher levels of some "classical" splice variants are associated with a better prognosis, while an increase in the "basal" isoform is conversely associated with a poor prognosis. These results suggest that splicing profiling has great potential in disease progression and in selecting the best for a particular patient.
Next, scientists began to study the molecular mechanisms that control the specific splicing of pancreatic tumor cell subtypes. They identified several splicing regulatory proteins that are differentially expressed in classical and basal-like tumors. Cell line experiments have shown that QKI proteins play a key role in establishing the splicing signature of aggressive basal-like isoforms.
QKI inhibits the splice variants typical of classical tumors and stimulates the incorporation of subtypes associated with a basal-like phenotype. Transcriptome analysis of QKI knockout in cell lines has identified hundreds of genes whose splicing is controlled by this protein. Many of these genes are involved in key processes in tumor development – changes in cell adhesion, migration, and metabolism.
The researchers also found specific binding sites for QKIs near their regulated exons and confirmed direct interactions with them in immunoprecipitation experiments of RNA-protein complexes. Small gene experiments with mutations at these sites demonstrate their critical role in QKI splicing regulation.
The role of QKI in determining the characterization of pancreatic tumor cells has been further investigated. This protein has been shown to facilitate the transition to a mesenchymal, more malleable state. When it shuts down, the cell retains more of its epithelial phenotype and loses its ability to actively migrate. On the contrary, its increased expression stimulates cell motility and other processes associated with epithelial-mesenchymal transition.
QKI also increases cancer cell resistance to chemotherapy, especially to irinotecan, which is included in the standard** regimen for pancreatic cancer. Conversely, a reduced level of sensitivity to the drug and an increase in its expression of QKI can lead to chemoresistance.
Importantly, elevated QKI levels were observed in poorly differentiated and metastatic tumors. Analysis of patient samples showed higher expression of this protein in metastases compared to primary tumors. In addition, QKI is more common in cells with high-grade malignancy compared to cells with moderate or low-grade malignancy.
Thus, the results of a comprehensive study suggest that QKI plays a key role in the acquisition of aggressiveness in pancreatic cancer cells, which determines poor prognosis and resistance to **. This protein establishes the splicing signature of basal-like tumor subtypes. It promotes the transformation of cells into a more malleable mesenchymal-like state, increasing the migratory activity of cells and resistance to antineoplastic drugs.
Increased QKI expression was observed during poorly differentiated tumors and metastases, consistent with its role in enhancing the malignant properties of cancer cells. The results obtained open up new opportunities for diagnosing pancreatic cancer. Analysis of the splicing signature and QKI expression of the tumor will allow us to more accurately determine the molecular subtype of the tumor and the prognosis of the patient.
In addition, the identified QKI-mediated splicing regulatory mechanisms may be the target of the development of new methods. Inhibition of this protein or correction of splicing signatures in cancer cells opens up ways to overcome its aggressiveness, resistance to ** and ultimately improve the prognosis of this serious disease.