Involvement of Differentially Expressed microRNAs in the PEGylated Liposome Encapsulated 188Rhenium-Mediated Suppression of Orthotopic Hypopharyngeal Tumor.

Bing-Ze Lin,Min-Ying Lin,Ting-Wen Chen,Muh-Hwa Yang,Yi-Jang Lee,Chih-Hsien Chang,Shen-Ying Wan

doi:10.3390/molecules25163609

Abstract

Hypopharyngeal cancer (HPC) accounts for the lowest survival rate among all types of head and neck cancers (HNSCC). However, the therapeutic approach for HPC still needs to be investigated. In this study, a theranostic 188Re-liposome was prepared to treat orthotopic HPC tumors and analyze the deregulated microRNA expressive profiles. The therapeutic efficacy of 188Re-liposome on HPC tumors was evaluated using bioluminescent imaging followed by next generation sequencing (NGS) analysis, in order to address the deregulated microRNAs and associated signaling pathways. The differentially expressed microRNAs were also confirmed using clinical HNSCC samples and clinical information from The Cancer Genome Atlas (TCGA) database. Repeated doses of 188Re-liposome were administrated to tumor-bearing mice, and the tumor growth was apparently suppressed after treatment. For NGS analysis, 13 and 9 microRNAs were respectively up-regulated and down-regulated when the cutoffs of fold change were set to 5. Additionally, miR-206-3p and miR-142-5p represented the highest fold of up-regulation and down-regulation by 188Re-liposome, respectively. According to Differentially Expressed MiRNAs in human Cancers (dbDEMC) analysis, most of 188Re-liposome up-regulated microRNAs were categorized as tumor suppressors, while down-regulated microRNAs were oncogenic. The KEGG pathway analysis showed that cancer-related pathways and olfactory and taste transduction accounted for the top pathways affected by 188Re-liposome. 188Re-liposome down-regulated microRNAs, including miR-143, miR-6723, miR-944, and miR-136 were associated with lower survival rates at a high expressive level. 188Re-liposome could suppress the HPC tumors in vivo, and the therapeutic efficacy was associated with the deregulation of microRNAs that could be considered as a prognostic factor.

Highlights

Hypopharyngeal cancer (HPC) represents malignant growth in the hypopharynx region and accounts for about 5% of all head and neck cancers (HNSCC) [1]
The timeline was schemed for the establishment of HPC tumor-bearing mice using FaDu-3R cells (Supplementary Figure S2), the administration of 188 Re-liposome, the optical imaging of tumor responses, tumor resection for RNA extraction, and next-generation sequencing (NGS) analysis (Figure 2A)
The growth of orthotopic tumors was significantly suppressed by 188 Re-liposome but not saline as detected using bioluminescent imaging (Figure 2B,C)

Summary

Introduction

Hypopharyngeal cancer (HPC) represents malignant growth in the hypopharynx region and accounts for about 5% of all head and neck cancers (HNSCC) [1]. As HPC is a rare cancer type with a late occurrence of symptoms and tumor spreading, it is not uncommon for it to be detected at advanced stages with a high mortality rate and poor prognosis [2]. HPC can be treated by conventional surgery, radiotherapy and chemotherapy, while radiotherapy alone is usually used at an early stage [3]. Several lines of evidence have claimed that a combination of radiotherapy and chemotherapy would provide better control of locoregional recurrence compared to surgical procedures [4,5]. A radiopharmaceutical named 99m Tc-MIBI (methoxy-isobutyl-isonitrile) has been reported to detect HPC with up to a 95% sensitivity using single photon emission computed tomography (SPECT) [6]. Nuclear medicine has not been reported to have assessed or monitored the efficacy of HPC therapy as mentioned above

Methods

Results

Conclusion