LncRNA‐CCAT5‐mediated crosstalk between Wnt/β‐Catenin and STAT3 signaling suggests novel therapeutic approaches for metastatic gastric cancer with high Wnt activity
Abstract Background Although the constitutively activated Wnt/β‐catenin signaling pathway plays vital roles in gastric cancer (GC) progression, few Wnt inhibitors are approved for clinical use. Additionally, the clinical significance of long non‐coding RNAs (lncRNAs) in GC intraperitoneal disseminat...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-01-01
|
| Series: | Cancer Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cac2.12507 |
| _version_ | 1797352863936020480 |
|---|---|
| author | Chenchen Liu Aiwen Shen Junquan Song Lei Cheng Meng Zhang Yanong Wang Xiaowen Liu |
| author_facet | Chenchen Liu Aiwen Shen Junquan Song Lei Cheng Meng Zhang Yanong Wang Xiaowen Liu |
| author_sort | Chenchen Liu |
| collection | DOAJ |
| description | Abstract Background Although the constitutively activated Wnt/β‐catenin signaling pathway plays vital roles in gastric cancer (GC) progression, few Wnt inhibitors are approved for clinical use. Additionally, the clinical significance of long non‐coding RNAs (lncRNAs) in GC intraperitoneal dissemination (IPD) remains elusive. Here, we investigated the function and therapeutic potential of Wnt‐transactivated lncRNA, colon cancer‐associated transcript 5 (CCAT5), in GC metastasis. Methods LncRNA‐sequencing assay was performed to document abundance changes of lncRNAs induced by Wnt family member 3A (Wnt3a) and degradation‐resistant β‐catenin (S33Y mutated) in ascites‐derived GC cells with low Wnt activity. Luciferase reporter, Chromatin immunoprecipitation (ChIP)‐re‐ChIP assays were performed to determine how CCAT5 was transcribed. The clinical significance of CCAT5 was examined in 2 cohorts of GC patients. The biological function of CCAT5 was investigated through gain‐ and loss‐of‐function studies. The molecular mechanism was explored through RNA‐sequencing, mass spectrometry, and CRISPR/Cas9‐knocknout system. The therapeutic potential of CCAT5 was examined through RNAi‐based cell xenograft model and patient‐derived xenograft (PDX) model of IPD. Results We identified a novel Wnt‐regulated lncRNA, CCAT5, which was transactivated by the β‐catenin/transcription factor 3 (TCF3) complex. CCAT5 was significantly upregulated in GC and predicted poor prognosis. Functional studies confirmed the promotive role of CCAT5 in GC growth and metastasis. Mechanistically, CCAT5 bound to the C‐end domain of signal transducer and activator of transcription 3 (STAT3) and blocks Src homology 2 domain‐containing protein tyrosine phosphatase 1 (SHP‐1)‐mediated STAT3Y705 dephosphorylation, leading to STAT3 nuclear entry and transactivation, thus accelerating GC progression. Furthermore, we demonstrated that both Wnt3a and β‐catenin acted as activator of STAT3 signaling pathway, and the interplay between CCAT5 and STAT3 was functionally essential for Wnt‐drived STAT3 signaling and tumor evolution. Finally, we revealed in vivo si‐CCAT5 selectively attenuated growth and metastasis of Wnthigh GC, but not Wntlow GC. The combination of si‐CCAT5 and oxaliplatin displayed obvious synergistic therapeutic effects on Wnthigh PDX mice. Conclusions We identified a novel Wnt‐transactivated lncRNA, CCAT5. Our study revealed a mechanism of STAT3 signaling regulation via canonical Wnt signaling and the functional significance of CCAT5 as critical mediator. We provided conceptual advance that lncRNAs serve as therapeutic targets reversing GC progression. |
| first_indexed | 2024-03-08T13:22:53Z |
| format | Article |
| id | doaj.art-a980998efde24d2e8f91ec0c88361f89 |
| institution | Directory Open Access Journal |
| issn | 2523-3548 |
| language | English |
| last_indexed | 2024-03-08T13:22:53Z |
| publishDate | 2024-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Communications |
| spelling | doaj.art-a980998efde24d2e8f91ec0c88361f892024-01-17T19:10:42ZengWileyCancer Communications2523-35482024-01-014417610010.1002/cac2.12507LncRNA‐CCAT5‐mediated crosstalk between Wnt/β‐Catenin and STAT3 signaling suggests novel therapeutic approaches for metastatic gastric cancer with high Wnt activityChenchen Liu0Aiwen Shen1Junquan Song2Lei Cheng3Meng Zhang4Yanong Wang5Xiaowen Liu6Department of Gastric Surgery Fudan University Shanghai Cancer Center Shanghai P. R. ChinaDepartment of Nephrology Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai P. R. ChinaDepartment of Gastric Surgery Fudan University Shanghai Cancer Center Shanghai P. R. ChinaDepartment of Pulmonary Shanghai Chest Hospital Shanghai Jiao Tong University Shanghai P. R. ChinaDepartment of Oncology Shanghai Medical College, Fudan University Shanghai P. R. ChinaDepartment of Gastric Surgery Fudan University Shanghai Cancer Center Shanghai P. R. ChinaDepartment of Gastric Surgery Fudan University Shanghai Cancer Center Shanghai P. R. ChinaAbstract Background Although the constitutively activated Wnt/β‐catenin signaling pathway plays vital roles in gastric cancer (GC) progression, few Wnt inhibitors are approved for clinical use. Additionally, the clinical significance of long non‐coding RNAs (lncRNAs) in GC intraperitoneal dissemination (IPD) remains elusive. Here, we investigated the function and therapeutic potential of Wnt‐transactivated lncRNA, colon cancer‐associated transcript 5 (CCAT5), in GC metastasis. Methods LncRNA‐sequencing assay was performed to document abundance changes of lncRNAs induced by Wnt family member 3A (Wnt3a) and degradation‐resistant β‐catenin (S33Y mutated) in ascites‐derived GC cells with low Wnt activity. Luciferase reporter, Chromatin immunoprecipitation (ChIP)‐re‐ChIP assays were performed to determine how CCAT5 was transcribed. The clinical significance of CCAT5 was examined in 2 cohorts of GC patients. The biological function of CCAT5 was investigated through gain‐ and loss‐of‐function studies. The molecular mechanism was explored through RNA‐sequencing, mass spectrometry, and CRISPR/Cas9‐knocknout system. The therapeutic potential of CCAT5 was examined through RNAi‐based cell xenograft model and patient‐derived xenograft (PDX) model of IPD. Results We identified a novel Wnt‐regulated lncRNA, CCAT5, which was transactivated by the β‐catenin/transcription factor 3 (TCF3) complex. CCAT5 was significantly upregulated in GC and predicted poor prognosis. Functional studies confirmed the promotive role of CCAT5 in GC growth and metastasis. Mechanistically, CCAT5 bound to the C‐end domain of signal transducer and activator of transcription 3 (STAT3) and blocks Src homology 2 domain‐containing protein tyrosine phosphatase 1 (SHP‐1)‐mediated STAT3Y705 dephosphorylation, leading to STAT3 nuclear entry and transactivation, thus accelerating GC progression. Furthermore, we demonstrated that both Wnt3a and β‐catenin acted as activator of STAT3 signaling pathway, and the interplay between CCAT5 and STAT3 was functionally essential for Wnt‐drived STAT3 signaling and tumor evolution. Finally, we revealed in vivo si‐CCAT5 selectively attenuated growth and metastasis of Wnthigh GC, but not Wntlow GC. The combination of si‐CCAT5 and oxaliplatin displayed obvious synergistic therapeutic effects on Wnthigh PDX mice. Conclusions We identified a novel Wnt‐transactivated lncRNA, CCAT5. Our study revealed a mechanism of STAT3 signaling regulation via canonical Wnt signaling and the functional significance of CCAT5 as critical mediator. We provided conceptual advance that lncRNAs serve as therapeutic targets reversing GC progression.https://doi.org/10.1002/cac2.12507CCAT5gastric cancerintraperitoneal disseminationSTAT3Wnt/β‐catenin |
| spellingShingle | Chenchen Liu Aiwen Shen Junquan Song Lei Cheng Meng Zhang Yanong Wang Xiaowen Liu LncRNA‐CCAT5‐mediated crosstalk between Wnt/β‐Catenin and STAT3 signaling suggests novel therapeutic approaches for metastatic gastric cancer with high Wnt activity Cancer Communications CCAT5 gastric cancer intraperitoneal dissemination STAT3 Wnt/β‐catenin |
| title | LncRNA‐CCAT5‐mediated crosstalk between Wnt/β‐Catenin and STAT3 signaling suggests novel therapeutic approaches for metastatic gastric cancer with high Wnt activity |
| title_full | LncRNA‐CCAT5‐mediated crosstalk between Wnt/β‐Catenin and STAT3 signaling suggests novel therapeutic approaches for metastatic gastric cancer with high Wnt activity |
| title_fullStr | LncRNA‐CCAT5‐mediated crosstalk between Wnt/β‐Catenin and STAT3 signaling suggests novel therapeutic approaches for metastatic gastric cancer with high Wnt activity |
| title_full_unstemmed | LncRNA‐CCAT5‐mediated crosstalk between Wnt/β‐Catenin and STAT3 signaling suggests novel therapeutic approaches for metastatic gastric cancer with high Wnt activity |
| title_short | LncRNA‐CCAT5‐mediated crosstalk between Wnt/β‐Catenin and STAT3 signaling suggests novel therapeutic approaches for metastatic gastric cancer with high Wnt activity |
| title_sort | lncrna ccat5 mediated crosstalk between wnt β catenin and stat3 signaling suggests novel therapeutic approaches for metastatic gastric cancer with high wnt activity |
| topic | CCAT5 gastric cancer intraperitoneal dissemination STAT3 Wnt/β‐catenin |
| url | https://doi.org/10.1002/cac2.12507 |
| work_keys_str_mv | AT chenchenliu lncrnaccat5mediatedcrosstalkbetweenwntbcateninandstat3signalingsuggestsnoveltherapeuticapproachesformetastaticgastriccancerwithhighwntactivity AT aiwenshen lncrnaccat5mediatedcrosstalkbetweenwntbcateninandstat3signalingsuggestsnoveltherapeuticapproachesformetastaticgastriccancerwithhighwntactivity AT junquansong lncrnaccat5mediatedcrosstalkbetweenwntbcateninandstat3signalingsuggestsnoveltherapeuticapproachesformetastaticgastriccancerwithhighwntactivity AT leicheng lncrnaccat5mediatedcrosstalkbetweenwntbcateninandstat3signalingsuggestsnoveltherapeuticapproachesformetastaticgastriccancerwithhighwntactivity AT mengzhang lncrnaccat5mediatedcrosstalkbetweenwntbcateninandstat3signalingsuggestsnoveltherapeuticapproachesformetastaticgastriccancerwithhighwntactivity AT yanongwang lncrnaccat5mediatedcrosstalkbetweenwntbcateninandstat3signalingsuggestsnoveltherapeuticapproachesformetastaticgastriccancerwithhighwntactivity AT xiaowenliu lncrnaccat5mediatedcrosstalkbetweenwntbcateninandstat3signalingsuggestsnoveltherapeuticapproachesformetastaticgastriccancerwithhighwntactivity |