DCBLD2 Affects the Development of Colorectal Cancer via EMT and Angiogenesis and Modulates 5-FU Drug Resistance
Pan Xie1,2, Fu-Qiang Yuan1,2, Ma-Sha Huang1,2
1Hunan Key Laboratory of Pharmacogenetics, Department of Clinical Pharmacology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
Abstract:
Background: DCBLD2 is highly expressed in various cancers, including colorectal cancer. DCBLD2 overexpression promotes tumor occurrence, development, and metastasis. However, DCBLD2 sensitivity to chemotherapy drugs and its mechanism on tumor development are unknown. Methods: DCBLD2 expression differences in cancer and normal tissues were obtained from GEO and TCGA databases. DCBLD2 influence on prognosis was also compared, and the database analysis results were verified via the analysis of clinical samples. GDSC database was used to analyze the effect of DCBLD2 expression difference on 5-FU drug sensitivity on tumor cells. CCK-8, clone formation, scratch, Transwell invasion and migration assays were used to assess DCBLD2 effects on the proliferation, metastasis, and 5-FU drug sensitivity on HCT116 and Caco-2 colorectal cancer cells. Angiogenesis and Matrigel plug assays were used to study the effect of DCBLD2 on angiogenesis. Q-RCR and Western Blot were used to analyze DCBLD2 impact on the EMT signaling pathway, and TAP-MS assay with Co-IP verification was used to identify the downstream target proteins binding to DCBLD2. Results: Both database and clinical sample validation results showed that the expression of DCBLD2 in colorectal cancer tissues was significantly higher than that in normal tissues, leading to poor prognosis of patients. GDSC database analysis showed that DCBLD2 overexpression caused tumor cell resistance to 5-FU. The results of in vitro and in vivo experiments showed that the inhibition of DCBLD2 reduced the proliferation, migration and invasion of colorectal cancer cells, inhibited the angiogenesis of endothelial cells, and enhanced the drug sensitivity to 5-FU. The results of q-RCR and Western Blot experiments showed that the inhibition of DCBLD2 can suppress the EMT signal. The results of TAP-MS assay showed that the proteins bound to DCBLD2 were enriched to the Focal adhesion pathway. The results of Co-IP assay show that DCBLD2 can combine with ITGB1, the key factor of Focal adhesion pathway. Conclusion: DCBLD2 may affect the development of colorectal cancer by regulating cell proliferation and motility, and modulate 5-FU resistance. Down-regulation of DCBLD2 can inhibit EMT signal and angiogenesis. DCBLD2 can combine with ITGB1, the key signal factor of the Focal adhesion pathway.
Insights
Overexpression of DCBLD2 in colorectal cancer promotes tumor growth and 5-FU resistance. Inhibiting DCBLD2 reduces tumor progression, angiogenesis, and enhances chemotherapy sensitivity by impacting the focal adhesion pathway.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- DCBLD2 is highly expressed in colorectal cancer, correlating with tumor progression and metastasis.
- The role of DCBLD2 in chemotherapy sensitivity and its precise mechanisms in tumorigenesis remain unclear.
Purpose of the Study:
- To investigate the role of DCBLD2 in colorectal cancer development, 5-fluorouracil (5-FU) sensitivity, and its underlying molecular mechanisms.
- To explore DCBLD2's impact on cell proliferation, migration, invasion, angiogenesis, and epithelial-mesenchymal transition (EMT).
Main Methods:
- Utilized GEO and TCGA databases for expression analysis and correlated DCBLD2 levels with patient prognosis.
- Performed in vitro (cell culture) and in vivo (animal models) experiments to assess DCBLD2's functional roles.
- Investigated DCBLD2's effect on 5-FU sensitivity, angiogenesis, EMT signaling, and identified binding proteins using techniques like CCK-8, Transwell assays, Western Blot, and TAP-MS with Co-IP.
Main Results:
- DCBLD2 expression is significantly elevated in colorectal cancer tissues compared to normal tissues, associated with poor prognosis.
- DCBLD2 overexpression confers resistance to 5-FU chemotherapy, while its inhibition enhances sensitivity.
- Inhibition of DCBLD2 suppressed tumor cell proliferation, migration, invasion, angiogenesis, and EMT, identifying ITGB1 in the focal adhesion pathway as a binding partner.
Conclusions:
- DCBLD2 plays a critical role in colorectal cancer progression by regulating proliferation, motility, and modulating 5-FU resistance.
- Down-regulation of DCBLD2 inhibits EMT and angiogenesis, suggesting therapeutic potential.
- DCBLD2 interacts with ITGB1, a key factor in the focal adhesion pathway, highlighting a novel mechanism in colorectal cancer development.
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