LIN28B promotes cell invasion and colorectal cancer metastasis via CLDN1 and NOTCH3
The RNA-binding protein LIN28B is overexpressed in over 30% of patients with colorectal cancer (CRC) and is associated with poor prognosis. In the present study, we unraveled a potentially novel mechanism by which LIN28B regulates colonic epithelial cell-cell junctions and CRC metastasis. Using huma...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2023-07-01
|
| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.167310 |
| _version_ | 1797634290991759360 |
|---|---|
| author | Kensuke Sugiura Yasunori Masuike Kensuke Suzuki Alice E. Shin Nozomu Sakai Hisahiro Matsubara Masayuki Otsuka Peter A. Sims Christopher J. Lengner Anil K. Rustgi |
| author_facet | Kensuke Sugiura Yasunori Masuike Kensuke Suzuki Alice E. Shin Nozomu Sakai Hisahiro Matsubara Masayuki Otsuka Peter A. Sims Christopher J. Lengner Anil K. Rustgi |
| author_sort | Kensuke Sugiura |
| collection | DOAJ |
| description | The RNA-binding protein LIN28B is overexpressed in over 30% of patients with colorectal cancer (CRC) and is associated with poor prognosis. In the present study, we unraveled a potentially novel mechanism by which LIN28B regulates colonic epithelial cell-cell junctions and CRC metastasis. Using human CRC cells (DLD-1, Caco-2, and LoVo) with either knockdown or overexpression of LIN28B, we identified claudin 1 (CLDN1) tight junction protein as a direct downstream target and effector of LIN28B. RNA immunoprecipitation revealed that LIN28B directly binds to and posttranscriptionally regulates CLDN1 mRNA. Furthermore, using in vitro assays and a potentially novel murine model of metastatic CRC, we show that LIN28B-mediated CLDN1 expression enhances collective invasion, cell migration, and metastatic liver tumor formation. Bulk RNA sequencing of the metastatic liver tumors identified NOTCH3 as a downstream effector of the LIN28B/CLDN1 axis. Additionally, genetic and pharmacologic manipulation of NOTCH3 signaling revealed that NOTCH3 was necessary for invasion and metastatic liver tumor formation. In summary, our results suggest that LIN28B promotes invasion and liver metastasis of CRC by posttranscriptionally regulating CLDN1 and activating NOTCH3 signaling. This discovery offers a promising new therapeutic option for metastatic CRC to the liver, an area where therapeutic advancements have been relatively scarce. |
| first_indexed | 2024-03-11T12:05:33Z |
| format | Article |
| id | doaj.art-4cc16e72c1d5417fbecfca91adb61af1 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:05:33Z |
| publishDate | 2023-07-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-4cc16e72c1d5417fbecfca91adb61af12023-11-07T16:25:54ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-07-01814LIN28B promotes cell invasion and colorectal cancer metastasis via CLDN1 and NOTCH3Kensuke SugiuraYasunori MasuikeKensuke SuzukiAlice E. ShinNozomu SakaiHisahiro MatsubaraMasayuki OtsukaPeter A. SimsChristopher J. LengnerAnil K. RustgiThe RNA-binding protein LIN28B is overexpressed in over 30% of patients with colorectal cancer (CRC) and is associated with poor prognosis. In the present study, we unraveled a potentially novel mechanism by which LIN28B regulates colonic epithelial cell-cell junctions and CRC metastasis. Using human CRC cells (DLD-1, Caco-2, and LoVo) with either knockdown or overexpression of LIN28B, we identified claudin 1 (CLDN1) tight junction protein as a direct downstream target and effector of LIN28B. RNA immunoprecipitation revealed that LIN28B directly binds to and posttranscriptionally regulates CLDN1 mRNA. Furthermore, using in vitro assays and a potentially novel murine model of metastatic CRC, we show that LIN28B-mediated CLDN1 expression enhances collective invasion, cell migration, and metastatic liver tumor formation. Bulk RNA sequencing of the metastatic liver tumors identified NOTCH3 as a downstream effector of the LIN28B/CLDN1 axis. Additionally, genetic and pharmacologic manipulation of NOTCH3 signaling revealed that NOTCH3 was necessary for invasion and metastatic liver tumor formation. In summary, our results suggest that LIN28B promotes invasion and liver metastasis of CRC by posttranscriptionally regulating CLDN1 and activating NOTCH3 signaling. This discovery offers a promising new therapeutic option for metastatic CRC to the liver, an area where therapeutic advancements have been relatively scarce.https://doi.org/10.1172/jci.insight.167310GastroenterologyOncology |
| spellingShingle | Kensuke Sugiura Yasunori Masuike Kensuke Suzuki Alice E. Shin Nozomu Sakai Hisahiro Matsubara Masayuki Otsuka Peter A. Sims Christopher J. Lengner Anil K. Rustgi LIN28B promotes cell invasion and colorectal cancer metastasis via CLDN1 and NOTCH3 JCI Insight Gastroenterology Oncology |
| title | LIN28B promotes cell invasion and colorectal cancer metastasis via CLDN1 and NOTCH3 |
| title_full | LIN28B promotes cell invasion and colorectal cancer metastasis via CLDN1 and NOTCH3 |
| title_fullStr | LIN28B promotes cell invasion and colorectal cancer metastasis via CLDN1 and NOTCH3 |
| title_full_unstemmed | LIN28B promotes cell invasion and colorectal cancer metastasis via CLDN1 and NOTCH3 |
| title_short | LIN28B promotes cell invasion and colorectal cancer metastasis via CLDN1 and NOTCH3 |
| title_sort | lin28b promotes cell invasion and colorectal cancer metastasis via cldn1 and notch3 |
| topic | Gastroenterology Oncology |
| url | https://doi.org/10.1172/jci.insight.167310 |
| work_keys_str_mv | AT kensukesugiura lin28bpromotescellinvasionandcolorectalcancermetastasisviacldn1andnotch3 AT yasunorimasuike lin28bpromotescellinvasionandcolorectalcancermetastasisviacldn1andnotch3 AT kensukesuzuki lin28bpromotescellinvasionandcolorectalcancermetastasisviacldn1andnotch3 AT aliceeshin lin28bpromotescellinvasionandcolorectalcancermetastasisviacldn1andnotch3 AT nozomusakai lin28bpromotescellinvasionandcolorectalcancermetastasisviacldn1andnotch3 AT hisahiromatsubara lin28bpromotescellinvasionandcolorectalcancermetastasisviacldn1andnotch3 AT masayukiotsuka lin28bpromotescellinvasionandcolorectalcancermetastasisviacldn1andnotch3 AT peterasims lin28bpromotescellinvasionandcolorectalcancermetastasisviacldn1andnotch3 AT christopherjlengner lin28bpromotescellinvasionandcolorectalcancermetastasisviacldn1andnotch3 AT anilkrustgi lin28bpromotescellinvasionandcolorectalcancermetastasisviacldn1andnotch3 |