Clinicopathological and Preclinical Patient-Derived Model Studies Define High Expression of NRN1 as a Diagnostic and Therapeutic Target for Clear Cell Renal Cell Carcinoma
BackgroundAcquired 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 neur...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-11-01
|
| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.758503/full |
| _version_ | 1818742872350916608 |
|---|---|
| author | Shuhei Kamada Shuhei Kamada Kazuhiro Ikeda Takashi Suzuki Wataru Sato Sachi Kitayama Satoru Kawakami Tomohiko Ichikawa Kuniko Horie Satoshi Inoue Satoshi Inoue |
| author_facet | Shuhei Kamada Shuhei Kamada Kazuhiro Ikeda Takashi Suzuki Wataru Sato Sachi Kitayama Satoru Kawakami Tomohiko Ichikawa Kuniko Horie Satoshi Inoue Satoshi Inoue |
| author_sort | Shuhei Kamada |
| collection | DOAJ |
| description | BackgroundAcquired 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.MethodsNRN1 expression in clinical RCC specimens was analyzed based on immunohistochemistry. NRN1-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.ResultsNRN1 immunoreactivity was positively associated with shorter overall survival in RCC patients. In TCGA RCC RNA-sequencing dataset, C-X-C chemokine receptor type 4 (CXCR4), a prognostic and stemness-related factor in RCC, is a gene whose expression is substantially correlated with NRN1 expression. Gain- and loss-of-function studies in RCC-PDC spheroid cultures revealed that NRN1 significantly promotes cell viability along with the upregulation of CXCR4. The NRN1-specific siRNA injection significantly suppressed the proliferation of RCC-PDC-derived xenograft tumors, in which CXCR4 expression is significantly repressed.ConclusionNRN1 can be a potential diagnostic and therapeutic target in RCC as analyzed by preclinical patient-derived cancer models and clinicopathological studies. |
| first_indexed | 2024-12-18T02:19:25Z |
| format | Article |
| id | doaj.art-e53d373d31574ad4a198a924982b9911 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-18T02:19:25Z |
| publishDate | 2021-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-e53d373d31574ad4a198a924982b99112022-12-21T21:24:18ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-11-011110.3389/fonc.2021.758503758503Clinicopathological and Preclinical Patient-Derived Model Studies Define High Expression of NRN1 as a Diagnostic and Therapeutic Target for Clear Cell Renal Cell CarcinomaShuhei Kamada0Shuhei Kamada1Kazuhiro Ikeda2Takashi Suzuki3Wataru Sato4Sachi Kitayama5Satoru Kawakami6Tomohiko Ichikawa7Kuniko Horie8Satoshi Inoue9Satoshi Inoue10Division of Systems Medicine & Gene Therapy, Saitama Medical University, Saitama, JapanDepartment of Urology, Graduate School of Medicine, Chiba University, Chiba, JapanDivision of Systems Medicine & Gene Therapy, Saitama Medical University, Saitama, JapanDepartment of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Miyagi, JapanDivision of Systems Medicine & Gene Therapy, Saitama Medical University, Saitama, JapanDivision of Systems Medicine & Gene Therapy, Saitama Medical University, Saitama, JapanDepartment of Urology, Saitama Medical Center, Saitama Medical University, Saitama, JapanDepartment of Urology, Graduate School of Medicine, Chiba University, Chiba, JapanDivision of Systems Medicine & Gene Therapy, Saitama Medical University, Saitama, JapanDivision of Systems Medicine & Gene Therapy, Saitama Medical University, Saitama, JapanDepartment of Systems Aging Science and Medicine, Tokyo Metropolitan Institute of Gerontology, Tokyo, JapanBackgroundAcquired 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.MethodsNRN1 expression in clinical RCC specimens was analyzed based on immunohistochemistry. NRN1-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.ResultsNRN1 immunoreactivity was positively associated with shorter overall survival in RCC patients. In TCGA RCC RNA-sequencing dataset, C-X-C chemokine receptor type 4 (CXCR4), a prognostic and stemness-related factor in RCC, is a gene whose expression is substantially correlated with NRN1 expression. Gain- and loss-of-function studies in RCC-PDC spheroid cultures revealed that NRN1 significantly promotes cell viability along with the upregulation of CXCR4. The NRN1-specific siRNA injection significantly suppressed the proliferation of RCC-PDC-derived xenograft tumors, in which CXCR4 expression is significantly repressed.ConclusionNRN1 can be a potential diagnostic and therapeutic target in RCC as analyzed by preclinical patient-derived cancer models and clinicopathological studies.https://www.frontiersin.org/articles/10.3389/fonc.2021.758503/fullrenal cell carcinomapatient-derived cancer cell (PDC)patient-derived xenograftcancer stem-like cellcancer stemnessspheroid |
| spellingShingle | Shuhei Kamada Shuhei Kamada Kazuhiro Ikeda Takashi Suzuki Wataru Sato Sachi Kitayama Satoru Kawakami Tomohiko Ichikawa Kuniko Horie Satoshi Inoue Satoshi Inoue Clinicopathological and Preclinical Patient-Derived Model Studies Define High Expression of NRN1 as a Diagnostic and Therapeutic Target for Clear Cell Renal Cell Carcinoma Frontiers in Oncology renal cell carcinoma patient-derived cancer cell (PDC) patient-derived xenograft cancer stem-like cell cancer stemness spheroid |
| 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 |
| title_full | Clinicopathological and Preclinical Patient-Derived Model Studies Define High Expression of NRN1 as a Diagnostic and Therapeutic Target for Clear Cell Renal Cell Carcinoma |
| title_fullStr | Clinicopathological and Preclinical Patient-Derived Model Studies Define High Expression of NRN1 as a Diagnostic and Therapeutic Target for Clear Cell Renal Cell Carcinoma |
| title_full_unstemmed | Clinicopathological and Preclinical Patient-Derived Model Studies Define High Expression of NRN1 as a Diagnostic and Therapeutic Target for Clear Cell Renal Cell Carcinoma |
| title_short | Clinicopathological and Preclinical Patient-Derived Model Studies Define High Expression of NRN1 as a Diagnostic and Therapeutic Target for Clear Cell Renal Cell Carcinoma |
| title_sort | clinicopathological and preclinical patient derived model studies define high expression of nrn1 as a diagnostic and therapeutic target for clear cell renal cell carcinoma |
| topic | renal cell carcinoma patient-derived cancer cell (PDC) patient-derived xenograft cancer stem-like cell cancer stemness spheroid |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.758503/full |
| work_keys_str_mv | AT shuheikamada clinicopathologicalandpreclinicalpatientderivedmodelstudiesdefinehighexpressionofnrn1asadiagnosticandtherapeutictargetforclearcellrenalcellcarcinoma AT shuheikamada clinicopathologicalandpreclinicalpatientderivedmodelstudiesdefinehighexpressionofnrn1asadiagnosticandtherapeutictargetforclearcellrenalcellcarcinoma AT kazuhiroikeda clinicopathologicalandpreclinicalpatientderivedmodelstudiesdefinehighexpressionofnrn1asadiagnosticandtherapeutictargetforclearcellrenalcellcarcinoma AT takashisuzuki clinicopathologicalandpreclinicalpatientderivedmodelstudiesdefinehighexpressionofnrn1asadiagnosticandtherapeutictargetforclearcellrenalcellcarcinoma AT watarusato clinicopathologicalandpreclinicalpatientderivedmodelstudiesdefinehighexpressionofnrn1asadiagnosticandtherapeutictargetforclearcellrenalcellcarcinoma AT sachikitayama clinicopathologicalandpreclinicalpatientderivedmodelstudiesdefinehighexpressionofnrn1asadiagnosticandtherapeutictargetforclearcellrenalcellcarcinoma AT satorukawakami clinicopathologicalandpreclinicalpatientderivedmodelstudiesdefinehighexpressionofnrn1asadiagnosticandtherapeutictargetforclearcellrenalcellcarcinoma AT tomohikoichikawa clinicopathologicalandpreclinicalpatientderivedmodelstudiesdefinehighexpressionofnrn1asadiagnosticandtherapeutictargetforclearcellrenalcellcarcinoma AT kunikohorie clinicopathologicalandpreclinicalpatientderivedmodelstudiesdefinehighexpressionofnrn1asadiagnosticandtherapeutictargetforclearcellrenalcellcarcinoma AT satoshiinoue clinicopathologicalandpreclinicalpatientderivedmodelstudiesdefinehighexpressionofnrn1asadiagnosticandtherapeutictargetforclearcellrenalcellcarcinoma AT satoshiinoue clinicopathologicalandpreclinicalpatientderivedmodelstudiesdefinehighexpressionofnrn1asadiagnosticandtherapeutictargetforclearcellrenalcellcarcinoma |