LATS1 exerts tumor suppressor functions via targeting Gli1 in colorectal cancer
Zhengchao Shen1, Yingying Pan2, Peng Chen1
1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, 241000, P.R. China.
Abstract:
Background: The Hippo pathway's primary kinase component, large tumor suppressor 1 (LATS1), has been hypothesized as a tumor suppressor in a variety of cancers. LATS1's biological effects on colorectal cancer (CRC) are yet to be determined. Methods: The analysis of LATS1 mRNA expression in CRC was conducted using public databases from the Gene Expressing Profiling Interactive Analysis database (GEPIA). Investigation for the expression of LATS1 protein in 102 CRC tumor tissues and 57 normal tissues was performed using immunohistochemistry (IHC) analysis. In vitro genetic manipulation was used to explore the potential role and mechanism of LATS1 in the regulation of proliferation and migration of CRC cells. Results: LATS1 was found to be considerably downregulated in CRC tissues, with much lower levels in individuals with bigger tumors of size (≥5 cm), deeper invasion (T3-4), positive lymph node metastasis (LNM), and advanced tumor-node-metastasis (TNM) stage (III-IV). As exhibited by clinical data analysis, LATS1 loss was significantly associated with TNM and LNM staging in CRC patients. Furthermore, our in vitro investigations revealed that LATS1 depletion increased CRC cell proliferation and migration in HCT116 cells, whereas overexpressing LATS1 had the opposite effect in SW620 cells. LATS1 suppressed the expression of glioma-associated oncogene-1 (Gli1), and LATS1's tumor-suppressive actions in CRC are dependent on Gli1. Moreover, LATS1 could modulate Yes-associated protein 1 (YAP1) expression and mTOR activation in CRC cells. Conclusion: Our findings identify the LATS1 as a unique Gli1 regulator in CRC cell migration and proliferation, and suggest that LATS1 may serve as a potential therapeutic target for CRC.
Insights
Large tumor suppressor 1 (LATS1) is downregulated in colorectal cancer (CRC), promoting tumor growth and metastasis. LATS1 loss is linked to advanced stages and influences Gli1, YAP1, and mTOR, suggesting LATS1 as a potential CRC therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- The Hippo pathway's kinase, large tumor suppressor 1 (LATS1), is a proposed tumor suppressor.
- LATS1's role in colorectal cancer (CRC) pathogenesis remains unclear.
- Understanding LATS1's function is crucial for developing novel CRC therapies.
Purpose of the Study:
- To investigate the expression and function of LATS1 in colorectal cancer.
- To determine the relationship between LATS1 expression and CRC clinical parameters.
- To elucidate the molecular mechanisms underlying LATS1's effects on CRC cell behavior.
Main Methods:
- Analysis of LATS1 mRNA expression in CRC using the GEPIA database.
- Immunohistochemistry (IHC) to assess LATS1 protein levels in tumor and normal tissues.
- In vitro studies involving genetic manipulation (depletion and overexpression) of LATS1 in CRC cell lines (HCT116, SW620).
Main Results:
- LATS1 expression is significantly downregulated in CRC tissues, correlating with larger tumor size, deeper invasion, lymph node metastasis, and advanced TNM stage.
- LATS1 depletion enhances CRC cell proliferation and migration, while LATS1 overexpression inhibits these processes.
- LATS1 suppresses glioma-associated oncogene-1 (Gli1) expression and modulates Yes-associated protein 1 (YAP1) and mTOR signaling pathways.
Conclusions:
- LATS1 acts as a tumor suppressor in colorectal cancer by regulating Gli1, YAP1, and mTOR.
- LATS1 downregulation is associated with aggressive clinicopathological features in CRC.
- LATS1 represents a promising therapeutic target for colorectal cancer treatment.
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