https://orcid.org/0000-0001-9914-5338
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Abstract
Aim
This article aimed to find appropriate pancreatic cancer (PC) patients to treat with Gemcitabine with better survival outcomes by detecting hENT1 levels.
Methods
We collected surgical pathological tissues from PC patients who received radical surgery in our hospital from September 2004 to December 2014. A total of 375 PC tissues and paired adjacent nontumor tissues were employed for the construction of 4 tissue microarrays (TMAs). The quality of the 4 TMAs was examined by HE staining. We performed immunohistochemistry analysis to evaluate hENT1 expression in the TMAs. Moreover, we detected hENT1 expression level and proved the role of hENT1 in cell proliferation, drug resistance, migration and invasion in vivo and vitro.
Results
The results indicated that low hENT1 expression indicated a significantly poor outcome in PC patients, including shortened DFS (21.6±2.8 months versus 36.9±4.0 months, p<0.001) and OS (33.6±3.9 versus 39.6±3.9, p=0.004). Meanwhile, patients in stage I/II of TNM stage had a longer OS (40.2±3.4 versus 15.4±1.7, p=0.002) and DFS (31.0±3.1 versus 12.4±1.9, p=0.016) than patients in stage III/IV. Patients in M0 stage had a longer OS (39.7±3.4 versus 16.2±1.9, p=0.026) and DFS(30.7±3.0 versus 11.8±2.2, p=0.031) than patients in M1 stage, and patients with tumors not invading the capsule had a better DFS than those with tumor invasion into the capsule (30.8±3.0 versus 12.6±2.3, p=0.053). Patients with preoperative CA19-9 values ≤467 U/mL have longer DFS than that of patients who had preoperative CA19-9 values >467 U/mL (37.9±4.1 versus 22.9±4.0, p=0.04). In the subgroup analysis, a high hENT1 expression level was related to a longer OS(39.4±4.0 versus 31.5±3.9, p=0.001) and DFS(35.7±4.0 versus 20.6±2.7; p<0.0001) in the Gemcitabine subgroup.
Conclusion
PC patients with high hENT1 expression have a better survival outcomes when receiving Gemcitabine. hENT1 expression can be a great prognostic indicator for PC patients to receive Gemcitabine treatment.
Abbreviations
PC, Pancreatic cancer; hENT1, human equilibrative nucleoside transporter 1; IHC, immunohistochemistry; TMAs, tissue microarrays.
Ethics Statement
All experiments were performed in compliance with the guidelines of the Institute of Laboratory Animals Science. All the data involved in the analysis of this paper has been collected from patients after signing the informed consent, which was audited by ethical committee of Peking UnionMedical College Hospital before the research began. The ethical batch number is I-23PJ1887. The pancreatic cancer cell lines were bought from American Type Culture Collection. Clinical samples in this study complies with the Declaration of Helsinki. All experiments were performed following PUMCH and national guidelines and regulations.
Acknowledgements
We would like to thank all laboratory members for their critical discussion of this manuscript.
Novelty & Impact Statements
This work further investigates the expression and prognostic features of human equilibrative nucleoside transporter 1 (hENT1) in pancreatic cancer patients extensively. Given the current situation that Gemcitabine is the preferred postoperative chemotherapy drug, using hENT1 as an index to distinguish those who are sensitive to Gemcitabine and predict the long-term prognosis of patients is very promising.
Author Contributions
Jianchun Xiao was responsible for the ethical review and the acquisition authorization of tissue specimens. Fangyu Zhao was responsible for the data analysis and processing of this article. Wenhao Luo was responsible for polishing the language, correcting grammatical errors, and submitting the article. Gang Yang was responsible for the animal experiment part of this article, including the entire process of the animal experiments, and the collection of tissue specimens, the tissue microarray, the immunohistochemical part and the in vitro experiment part. All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors declare no potential conflicts of interest in this work.