05018820

July 14, 2025, 11:18

Reader’s expertise on the topic of the manuscript

Does the reader have a conflict of interest?

The overall quality of the manuscript, based on the above-listed criteria, should be evaluated and classified according to the following five categories

Language quality (style, grammar, and spelling) should be evaluated and classified according to the following five categories.

To the Editor, We read with great interest the article by Ren et al. [1], published in World Journal of Gastroenterology, which investigates serum exosomal hsa-let-7f-5p as a potential non-invasive biomarker for detecting metastatic pancreatic cancer. The research presents a compelling advancement in the molecular diagnostics of one of the most aggressive malignancies. This study is both timely and relevant, considering the dismal survival rates in pancreatic cancer due to delayed diagnosis and poor response to conventional therapies [1, 2]. In this letter, we aim to provide a critical appraisal of the study design and methodology, place the findings in the context of the current scientific literature, evaluate the novelty and translational potential of hsa-let-7f-5p, and recommend avenues for future research. Ren et al. successfully shown that hsa-let-7f-5p is considerably higher in the serum exosomes of patients with metastatic pancreatic cancer than in those with localized illness. They discovered 42 differently expressed miRNAs using high-throughput sequencing and verified hsa-let-7f-5p using qRT-PCR, providing strong support for their result. These findings are consistent with a growing body of data that exosomal miRNAs, due to their stability in circulation and tumor selectivity, have intriguing diagnostic capacities in malignancies [3-5]. The reason for using serum exosomal miRNAs as biomarkers is widely understood. Exosomes are small vesicles released by nearly all cells, including tumor cells, that carry molecular cargo specific to their cell of origin. Previous research has demonstrated the usage of exosomal miRNAs such as miR-21, miR-1246, and miR-10b in pancreatic cancer [6-8]. However, few studies have focused on distinguishing metastatic from non-metastatic pancreatic cancer, which is an important clinical differential. One of the major strengths of Ren et al.'s work is the comprehensive pipeline employed for exosome isolation, characterization, and miRNA profiling. The authors validated exosomes using well-established techniques such as transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blotting. This multiparametric validation boosts the credibility of their results. The let-7 family of miRNAs is known for its tumor-suppressive and context-dependent oncogenic roles. While most members inhibit proliferation and metastasis, emerging evidence shows that specific let-7 members, such as let-7f-5p, can be upregulated in certain cancers and are associated with worse outcomes [9]. Ma et al. reported that hsa-let-7f-5p was highly expressed in pulmonary carcinoid tumors and regulated HMGA2, a protein involved in chromatin remodeling and EMT [10]. In prostate cancer, Valera et al. found higher hsa-let-7f-5p expression in older patients, suggesting its possible role in tumor progression with age [11]. Ren et al.’s results extend these findings to pancreatic cancer, highlighting the utility of hsa-let-7f-5p as a stage-specific biomarker rather than merely a diagnostic one. The strength of hsa-let-7f-5p as a diagnostic marker for metastasis is promising, but a comparative evaluation with other known biomarkers would enrich the discussion. For instance: miR-21 has been extensively validated as an oncogenic miRNA in pancreatic cancer and is known to promote invasion and resistance to gemcitabine [12]. miR-155 and miR-196a have been associated with poor prognosis and have been considered for early diagnostic panels [13]. In this investigation, I discovered many weaknesses. The first is a small sample size (n=36), and the lack of longitudinal follow-up data limits the findings' generalizability and prognostic application. Multicenter trials with larger and more diverse cohorts are required to verify hsa-let-7f-5p as a clinical biomarker. Furthermore, only four miRNAs were validated, leaving the other 38 (including 34 unique ones) untested. Some of these may have even greater discriminatory strength or synergistic benefit when integrated into multi-miRNA signatures, a method that has demonstrated increased accuracy in other malignancies. Moreover, the biological activities of hsa-let-7f-5p in encouraging metastasis warrant additional investigation. Functional research using in vitro invasion tests and in vivo metastasis models could help determine whether this miRNA is simply a marker or a mechanistic component to metastatic spread. Another topic to look at is if exosomal hsa-let-7f-5p levels alter in response to treatment. If so, this could lead to real-time, non-invasive therapy monitoring, which is critical in pancreatic oncology. The authors recommend using hsa-let-7f-5p in routine surveillance to detect metastases in pancreatic cancer patients, possibly in conjunction with imaging. We support this objective and urge that commercial assay kits be developed and clinically validated in accordance with CLIA/CAP requirements. Given that the majority of pancreatic cancer patients come with late-stage disease, a non-invasive technology for early detection of metastases can have a considerable impact on treatment decisions, such as avoiding non-curative surgery or starting systemic therapy earlier. Furthermore, including such biomarkers into AI-driven diagnostic pipelines has the potential to improve risk classification algorithms and customize treatment regimens, in line with precision medicine concepts. Ren et al. provide a valuable contribution to the field by identifying serum exosomal hsa-let-7f-5p as a potential diagnostic biomarker for metastatic pancreatic cancer. The study is technically sound, analytically robust, and biologically plausible. Nevertheless, broader validation, mechanistic studies, and clinical comparisons with existing biomarkers are necessary to cement its place in clinical practice. We commend the authors for their innovative and methodologically rigorous work and look forward to seeing the next phase of this research. Their findings not only enhance our understanding of pancreatic cancer metastasis but also pave the way for more personalized, non-invasive diagnostic tools in oncology. Reference: 1. Verma, H.K., et al., A Retrospective Look at Anti-EGFR Agents in Pancreatic Cancer Therapy. Curr Drug Metab, 2019. 20(12): p. 958-966. 2. Golivi, Y., et al., Small molecular inhibitors: Therapeutic strategies for pancreatic cancer. Drug Discovery Today, 2024. 29(7): p. 104053. 3. Wu, J. and Z. Shen, Exosomal miRNAs as biomarkers for diagnostic and prognostic in lung cancer. Cancer Med, 2020. 9(19): p. 6909-6922. 4. Lohajová Behulová, R., et al., Circulating exosomal miRNAs as a promising diagnostic biomarker in cancer. Physiol Res, 2023. 72(S3): p. S193-s207. 5. Li, C., et al., The role of Exosomal miRNAs in cancer. Journal of Translational Medicine, 2022. 20(1): p. 6. 6. Uddin, M.H., et al., Exosomal microRNA in Pancreatic Cancer Diagnosis, Prognosis, and Treatment: From Bench to Bedside. Cancers (Basel), 2021. 13(11). 7. Jafari, A., et al., The Emerging Role of Exosomal miRNAs as Biomarkers for Early Cancer Detection: A Comprehensive Literature Review. Technol Cancer Res Treat, 2023. 22: p. 15330338231205999. 8. Xu, Y., et al., The role of exosomal microRNAs in pancreatic cancer. Stem Cell Investigation, 2020. 7. 9. Gilles, M.E. and F.J. Slack, Let-7 microRNA as a potential therapeutic target with implications for immunotherapy. Expert Opin Ther Targets, 2018. 22(11): p. 929-939. 10. Ma, Q., et al., HMGA2 promotes cancer metastasis by regulating epithelial-mesenchymal transition. Front Oncol, 2024. 14: p. 1320887. 11. Valera, V.A., et al., microRNA Expression Profiling in Young Prostate Cancer Patients. J Cancer, 2020. 11(14): p. 4106-4114. 12. Chen, C., L. Demirkhanyan, and C.S. Gondi, The Multifaceted Role of miR-21 in Pancreatic Cancers. Cells, 2024. 13(11). 13. Yuan, W., et al., New combined microRNA and protein plasmatic biomarker panel for pancreatic cancer. Oncotarget, 2016. 7(48).

First, thank you very much for your professional comments on the article published in World Journal of Gastroenterology. Second, we read your comments with great interest. You are welcome to format your valuable comments into a Letter to the Editor and submit it online to World Journal of Gastroenterology at https://www.f6publishing.com. There are no restrictions on the number of words, figures (color, B/W) or authors for a Letter to the Editor. In addition, the article processing charge will be exempted for this Letter to the Editor. As with all articles published by the Baishideng Publishing Group, the Letter to the Editor will be published online after completing peer review. The guidelines for a Letter to the Editor can be found at: https://www.wjgnet.com/bpg/GerInfo/219. Finally, we look forward to receiving your high-quality Letter to the Editor, which will promote academic communication and lead the development of this discipline.