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Resistance to trastuzumab, which specifically target HER2-positive breast and gastric cancer, can develop ultimately in cancer patients. However, the underlying mechanisms of resistance in gastric cancer have not been fully elucidated. Here, we established trastuzumab-resistant MKN45 and NCI N87 gastric cancer sublines from their parental cells. The resistant cells exhibited characteristics of epithelial-mesenchymal transition (EMT) and acquired higher migratory and invasive capacities. To exploit the activated pathways and develop new strategies to overcome trastuzumab resistance, we investigated MKN45 and MKN45/R cells via label-free quantitative proteomics, and found pathways that were altered significantly in MKN45/R cells, with the Wnt/β-catenin pathway being the most significant. We further confirmed the activation of this pathway by detecting its key molecules in MKN45/R and NCI N87/R cells via Western blot, in which Wnt3A, FZD6, and CTNNB1 increased, whereas GSK-3β decreased, manifesting the activation of the Wnt/β-catenin pathway. Correspondingly, inhibition of Wnt/β-catenin pathway by ICG-001, a specific Wnt/β-catenin inhibitor, preferentially reduced proliferation and invasion of trastuzumab-resistant cells and reversed EMT. Concurringly, CTNNB1 knockdown in stable cell lines potently sensitized cells to trastuzumab and induced more apoptosis. Taken together, our study demonstrates that the Wnt/β-catenin pathway mediates trastuzumab resistance, and the combination of Wnt/β-catenin inhibitors with trastuzumab may be an effective treatment option. [ABSTRACT FROM AUTHOR]

Background: This study aimed to evaluate the relationship between LINC00665 expression levels and the risk of hepatocellular carcinoma (HCC) in Chinese Han nationality patients and to explore the influence of LINC00665 dysregulation on the proliferation and migration potential of HCC cells., Patients and Methods: We investigated the expression of LINC00665 in The Cancer Genome Atlas (TCGA) database. Then, we confirmed the expression of LINC00665 in 54 pairs of surgical tissues from HCC patients and in liver cancer cell lines by quantitative real-time polymerase chain reaction. Furthermore, we manipulated the expression level of LINC00665 and examined the cell proliferation and migration abilities of HCC cells., Results: In the TCGA cohort, a high level of LINC00665 in patients with HCC was significantly associated with tumor stage, tumor differentiation grade, and overall survival. In our HCC patient cohort, overexpression of LINC00665 in patients showed positive correlations with alpha-fetoprotein level, Barcelona Clinic Liver Cancer stage, and tumor differentiation grade. In addition, LINC00665 was upregulated in HCC cells, especially in cells with rapid growth rates and high migration abilities. A new LINC00665 isoform with a length of 1,371 nucleotides was identified in MHCC-97H cells. Interfering with LINC00665 expression weakened the proliferation and migration abilities of HCC cells. In contrast, LINC00665 overexpression enhanced proliferation and migration abilities., Conclusion: LINC00665 was upregulated in HCC tissues and cells and might be used to predict a poor prognosis of HCC patients. In addition, LINC00665 may promote the malignant progression of HCC by enhancing proliferation and migration capacities., Competing Interests: None., (IJCEP Copyright © 2023.)