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Decoding the Significance of Amino Acid-dependent Signal Recognition Particle 9 Nuclear Translocation: Implications for Pancreatic Cancer Prognosis and Functionality [RIP-seq]

ABSTRACT: Signal recognition particles (SRPs) are important components in regulating intracellular protein transport and secretion, and tumors with high expression of Signal recognition particle 9 (SRP9) have tended to have poorer overall survival, although no reports have described the relationship between its localization and prognosis in pancreatic cancer. We conducted immunohistochemical staining for SRP9 for excised specimens from pancreatic cancer surgery cases without preoperative chemotherapy or radiotherapy performed. We found that in some cases SRP9 was preferentially expressed in the nucleus of the cancerous regions, which was hardly detected in other cases, suggesting SRP9 was transported to nucleus in the former cases. Therefore, the prognosis of patients with SRP9 nuclear translocation was compared by dividing them into two groups: those with a nuclear translocation rate of >50% and ≤50%. Patients with a nuclear translocation rate of >50% had significantly better recurrence-free survival compared with nuclear translocation rate of ≤50% group (p = 0.037). Subsequent in vitro experiments also showed that its nuclear translocation rate is reduced under amino acid deficient conditions. Further, to investigate the mechanism of SRP9 nuclear translocation, we studied in vitro by introducing the genes of SRP9 splicing variants (v1 and v2) and their deletion mutants lacking C-terminal regions into MiaPaCa pancreatic cancer cells. As a result, it was confirmed that both splicing variants showed nuclear translocation regardless of C-terminal deletions. Taking advantage of the fact that SRP9 is an RNA-binding protein, we next decided to sequence RNAs that bind to nuclear translocated v1 and v2 and evaluate their function in nuclear translocation. RNA Immunoprecipitation Sequencing of nuclear translocated v1 and v2 showed that pathways involved in cancer progression and protein translation were downregulated. The further study of nuclear translocation of SRP9 may open an avenue to optimization of precise evaluation and therapeutic control of pancreatic cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE246628 | GEO | 2024/01/12

REPOSITORIES: GEO

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Project description:Purpose: Chemotherapy is pivotal in the multimodal treatment of pancreatic cancer patients. In recent years, technical advances have developed experimental methods that unveiled a high degree of inter- and intratumoral heterogeneity in pancreatic cancer. We hypothesized that intratumoral heterogeneity (ITH) impacts response to gemcitabine treatment and demands specific targeting of resistant subclones. Experimental Design: We addressed the effect of ITH on response to gemcitabine treatment using single cell-derived cell lines (SCDCL) from the classical-like cell line BxPC3 and the basal-like cell line Panc-1 which were analyzed by mRNA-seq and mass spectrometry. Results: Individual SCDCLs of the parental tumor cell populations of BxPC3 and Panc-1 showed considerable heterogeneity in response to gemcitabine. Unsupervised principal component analysis (PCA) including the 1,000 most variably expressed genes showed a clustering of the SCDCLs according to their respective sensitivity to gemcitabine treatment for BxPC3, while this clustering was less clear for Panc-1. In BxPC3 SCDCLs, enriched signaling pathways EMT, TNF signaling via NfKB, and IL2STAT5 signaling correlated with more resistant behavior to gemcitabine. In Panc-1 SCDCLs MYC targets V1 and V2 as well as E2F targets were associated with stronger resistance to gemcitabine. Feature extraction of proteomes again identified less proteins whose expression was associated with the response of individual SCDCLs in Panc-1 compared to BxPC3. Based on molecular profiles, we could show that the gemcitabine-resistant SCDCLs of both BxPC3 and Panc-1 are more sensitive to the BET inhibitor JQ1 compared to the respective gemcitabine-sensitive SCDCLs. Conclusions: Our model system of SCDCLs identified gemcitabine-resistant subclones within a parental tumor population and provides evidence for the critical role of ITH for treatment response in pancreatic cancer. Through molecular profiling, we identified specific signaling pathways and protein signatures that might help to explain the differential response to treatment among clones. We exploited these molecular differences for an improved and more targeted therapy of resistant subclones of a heterogeneous tumor.

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Decoding the Significance of Amino Acid-dependent Signal Recognition Particle 9 Nuclear Translocation: Implications for Pancreatic Cancer Prognosis and Functionality [RIP-seq]

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