<scp>REG3A</scp> promotes proliferation and <scp>DDP</scp> resistance of ovarian cancer cells by activating the <scp>PI3K</scp>/Akt signaling pathway

Jiang, Lingling; Liu, Yinglei; Liu, Manhua; Zheng, Yanli; Chen, Liping; Shan, Feng; Ji, Jinlong; Cao, Yang; Kai, Haili; Kang, Xinyi

doi:10.1002/tox.23952

Cited by 4 publications

(1 citation statement)

References 34 publications

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“…Ye et al reported a positive correlation between REG3A overexpression and increased Akt phosphorylation in colorectal cancer cells [ 15 ]. A recent study by Jiang and colleagues reported that REG3A enhanced the proliferation of ovarian cancer cells through activating PI3K/Akt signaling pathway [ 47 ]. Additionally, REG3A is involved in the activation of the Akt cascade in glioma cells [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Increased expression of REG3A promotes tumorigenic behavior in triple negative breast cancer cells

Jin,

Yang,

et al. 2024

Breast Cancer Res

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Background Identifying new targets in triple negative breast cancer (TNBC) remains critical. REG3A (regenerating islet-derived protein 3 A), a calcium-dependent lectin protein, was thoroughly investigated for its expression and functions in breast cancer. Methods Bioinformatics and local tissue analyses were employed to identify REG3A expression in breast cancer. Genetic techniques were employed to modify REG3A expression, and the resulting effects on the behaviors of breast cancer cells were examined. Subcutaneous xenograft models were established to investigate the involvement of REG3A in the in vivo growth of breast cancer cells. Results Analysis of the TCGA database uncovered increased REG3A levels in human breast cancer tissues. Additionally, REG3A mRNA and protein levels were elevated in TNBC tissues of locally treated patients, contrasting with low expression in adjacent normal tissues. In primary human TNBC cells REG3A shRNA notably hindered cell proliferation, migration, and invasion while triggering caspase-mediated apoptosis. Similarly, employing CRISPR-sgRNA for REG3A knockout showed significant anti-TNBC cell activity. Conversely, REG3A overexpression bolstered cell proliferation and migration. REG3A proved crucial for activating the Akt-mTOR cascade, as evidenced by decreased Akt-S6K1 phosphorylation upon REG3A silencing or knockout, which was reversed by REG3A overexpression. A constitutively active mutant S473D Akt1 (caAkt1) restored Akt-mTOR activation and counteracted the proliferation inhibition and apoptosis induced by REG3A knockdown in breast cancer cells. Crucially, REG3A played a key role in maintaining mTOR complex integrity. Bioinformatics identified zinc finger protein 680 (ZNF680) as a potential REG3A transcription factor. Knocking down or knocking out ZNF680 reduced REG3A expression, while its overexpression increased it in primary breast cancer cells. Additionally, enhanced binding between ZNF680 protein and the REG3A promoter was observed in breast cancer tissues and cells. In vivo, REG3A shRNA significantly inhibited primary TNBC cell xenograft growth. In REG3A-silenced xenograft tissues, reduced REG3A levels, Akt-mTOR inhibition, and activated apoptosis were evident. Conclusion ZNF680-caused REG3A overexpression drives tumorigenesis in breast cancer possibly by stimulating Akt-mTOR activation, emerging as a promising and innovative cancer target.

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Section: Discussionmentioning

confidence: 99%

Increased expression of REG3A promotes tumorigenic behavior in triple negative breast cancer cells

Jin,

Yang,

et al. 2024

Breast Cancer Res

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Anti-proliferation effect of chitooligosaccharide on colitis-associated cancer in mice: Possible involvement of miRNA-155/TLR4/Reg3g pathway

Liu,

Ma,

Guo

et al. 2024

Journal of Functional Foods

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Increased expression of REG3A promotes tumorigenic behavior in triple negative breast cancer cells

Jin,

Yang,

et al. 2024

Preprint

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Background: Identifying new targets in triple negative breast cancer (TNBC) remains critical. REG3A (regenerating islet-derived protein 3A), a calcium-dependent lectin protein, was thoroughly investigated for its expression and functions in breast cancer. Methods: Bioinformatics and local tissue analyses were employed to identify REG3A expression in breast cancer. Genetic techniques were employed to modify REG3A expression, and the resulting effects on the behaviors of breast cancer cells were examined. Subcutaneous xenograft models were established to investigate the involvement of REG3A in the in vivo growth of breast cancer cells. Results: Analysis of the TCGA database uncovered increased REG3A levels in human breast cancer tissues. Additionally, REG3AmRNA and protein levels were elevated in TNBC tissues of locally treated patients, contrasting with low expression in adjacent normal tissues. In primary human TNBC cells REG3A shRNA notably hindered cell proliferation, migration, and invasion while triggering caspase-mediated apoptosis. Similarly, employing CRISPR-sgRNA for REG3A knockout showed significant anti-TNBC cell activity. Conversely, REG3A overexpression bolstered cell proliferation and migration. REG3A proved crucial for activating the Akt-mTOR cascade, as evidenced by decreased Akt-S6K1 phosphorylation upon REG3A silencing or knockout, which was reversed by REG3A overexpression. A constitutively active mutant S473D Akt1 (caAkt1) restored Akt-mTOR activation and counteracted the proliferation inhibition and apoptosis induced by REG3A knockdown in breast cancer cells. Crucially, REG3A played a key role in maintaining mTOR complex integrity. Bioinformatics identified zinc finger protein 680 (ZNF680) as a potential REG3A transcription factor. Knocking down or knocking out ZNF680 reduced REG3A expression, while its overexpression increased it in primary breast cancer cells. Additionally, enhanced binding between ZNF680 protein and the REG3A promoter was observed in breast cancer tissues and cells. In vivo, REG3A shRNA significantly inhibited primary TNBC cell xenograft growth. In REG3A-silenced xenograft tissues, reduced REG3A levels, Akt-mTOR inhibition, and activated apoptosis were evident. Conclusion: ZNF680-caused REG3A overexpression drives tumorigenesis in breast cancer possibly by stimulating Akt-mTOR activation, emerging as a promising and innovative cancer target.

show abstract

REG3A promotes proliferation and DDP resistance of ovarian cancer cells by activating the PI3K/Akt signaling pathway

Cited by 4 publications

References 34 publications

Increased expression of REG3A promotes tumorigenic behavior in triple negative breast cancer cells

Increased expression of REG3A promotes tumorigenic behavior in triple negative breast cancer cells

Anti-proliferation effect of chitooligosaccharide on colitis-associated cancer in mice: Possible involvement of miRNA-155/TLR4/Reg3g pathway

Increased expression of REG3A promotes tumorigenic behavior in triple negative breast cancer cells

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