AUTHOR=Kamada Shuhei , Ikeda Kazuhiro , Suzuki Takashi , Sato Wataru , Kitayama Sachi , Kawakami Satoru , Ichikawa Tomohiko , Horie Kuniko , Inoue Satoshi 

TITLE=Clinicopathological and Preclinical Patient-Derived Model Studies Define High Expression of NRN1 as a Diagnostic and Therapeutic Target for Clear Cell Renal Cell Carcinoma

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.758503

DOI=10.3389/fonc.2021.758503

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>Acquired therapeutic resistance and metastasis/recurrence remain significant challenge in advance renal cell carcinoma (RCC), thus the establishment of patient-derived cancer models may provide a clue to assess the problem. We recently characterized that neuritogenesis-related protein neuritin 1 (NRN1) functions as an oncogene in testicular germ cell tumor. This study aims to elucidate the role of NRN1 in RCC.</p></sec><sec><title>Methods</title><p>NRN1 expression in clinical RCC specimens was analyzed based on immunohistochemistry. <italic>NRN1</italic>-associated genes in RCC were screened by the RNA-sequencing dataset from The Cancer Genome Atlas (TCGA). RCC patient-derived cancer cell (RCC-PDC) spheroid cultures were established and their viabilities were evaluated under the condition of gene silencing/overexpression. The therapeutic effect of NRN1-specific siRNA was evaluated in RCC-PDC xenograft models.</p></sec><sec><title>Results</title><p>NRN1 immunoreactivity was positively associated with shorter overall survival in RCC patients. In TCGA RCC RNA-sequencing dataset, <italic>C-X-C chemokine receptor type 4</italic> (<italic>CXCR4</italic>), a prognostic and stemness-related factor in RCC, is a gene whose expression is substantially correlated with <italic>NRN1</italic> expression. Gain- and loss-of-function studies in RCC-PDC spheroid cultures revealed that <italic>NRN1</italic> significantly promotes cell viability along with the upregulation of <italic>CXCR4</italic>. The NRN1-specific siRNA injection significantly suppressed the proliferation of RCC-PDC-derived xenograft tumors, in which <italic>CXCR4</italic> expression is significantly repressed.</p></sec><sec><title>Conclusion</title><p>NRN1 can be a potential diagnostic and therapeutic target in RCC as analyzed by preclinical patient-derived cancer models and clinicopathological studies.</p></sec>