FOXD3 and GAB2 as a pair of rivals antagonistically control hepatocellular carcinogenesis

Liu, Ruimin; Sun, Yan; Chen, Shuai; Hong, Yun Yu; Lu, Zhongxian

doi:10.1111/febs.16403

Cited by 2 publications

(3 citation statements)

References 47 publications

(90 reference statements)

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“…The pivotal role of Gab2, a molecule associated with tumor growth, progression and metastasis ( 29 , 18 ), has been highlighted in recent studies examining its dysregulated expression across several human cancers, including BRCA ( 21 ), OV ( 22 , 23 ), HCC ( 24 , 25 ), CRC ( 26 ) and melanoma ( 27 ), as well as its potential as a novel oncogene. A previous study by the authors demonstrated a high expression of Gab2 in CRC tissues and cell lines, particularly in specimens from patients with CRC with metastases ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

“…This family of proteins represents a class of substrate molecules that can associate with tyrosine kinase through the recruitment of signaling molecules rich in phosphotyrosine domains, participating in the activation and transduction of numerous signaling pathways, playing a critical role in cellular physiological processes, such as differentiation, proliferation, migration and apoptosis ( 18 ). Previous studies have discovered a marked elevated expression of Gab2 in leukemia ( 19 , 20 ) and several human malignancies, such as breast cancer (BRCA) ( 21 ), ovarian cancer (OV) ( 22 , 23 ), hepatocellular carcinoma (HCC) ( 24 , 25 ), CRC ( 26 ) and melanoma ( 27 ), indicating its potential significance in oncologic progression. However, the impact and mechanisms of action of Gab2 on TAM polarization remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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Gab2 promotes the growth of colorectal cancer by regulating the M2 polarization of tumor‑associated macrophages

Gao,

Long,

Qin

et al. 2023

Int J Mol Med

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Tumor-associated macrophages (TAMs) are pivotal components in colorectal cancer (CRC) progression, markedly influencing the tumor microenvironment through their polarization into the pro-inflammatory M1 or pro-tumorigenic M2 phenotypes. Recent studies have highlighted that the Grb2-associated binder 2 (Gab2) is a critical gene involved in the development of various types of tumor, including CRC. However, the precise role of Gab2 in mediating TAM polarization remains incompletely elucidated. In the present study, it was discovered that Gab2 was highly expressed within CRC tissue TAMs, and was associated with a poor prognosis of patients with CRC. Functionally, it was identified that the tumor-conditioned medium (TCM) induced Gab2 expression, facilitating the TAMs towards an M2-like phenotype polarization. Of note, the suppression of Gab2 expression using shRNA markedly inhibited the TCM-induced expression of M2-associated molecules, without affecting M1-type markers. Furthermore, the xenotransplantation model demonstrated that Gab2 deficiency in TAMs inhibited tumor growth in the mouse model of CRC. Mechanistically, Gab2 induced the M2 polarization of TAMs by regulating the AKT and ERK signaling pathways, promoting CRC growth and metastasis. In summary, the present study study elucidates that decreasing Gab2 expression hinders the transition of TAMs towards the M2 phenotype, thereby suppressing the growth of CRC. The exploration of the regulatory mechanisms of Gab2 in TAM polarization may enhance the current understanding of the core molecular pathways of CRC development and may thus provide a foundation for the development of novel immunotherapeutic strategies targeted against TAMs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gab2 promotes the growth of colorectal cancer by regulating the M2 polarization of tumor‑associated macrophages

Gao,

Long,

Qin

et al. 2023

Int J Mol Med

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“…The migration of HepG2 cells was analyzed using Transwell chambers according to a previous description [ 28 ]. Frist, 1 × 10 5 HepG2 cells were cultured in the upper chambers of Transwells in a growth medium at 37 °C with 5% CO 2 for 28 h. Then, the chambers were washed two times with PBS, and the cells were fixed with formaldehyde for 10 min.…”

Section: Methodsmentioning

confidence: 99%

miR-9 and miR-181a Target Gab2 to Inhibit the Proliferation and Migration of Hepatocellular Carcinoma HepG2 Cells

Huang

Liu

Zhou

et al. 2022

Genes

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The incidence of liver cancer ranks seventh globally, with nearly half of all cases occurring in East Asia, but currently, there are very few drugs to treat it. Our previous studies demonstrated that the signal integration protein Gab2 is a potential drug target for the prevention and therapy of liver cancer. Here, we screened for and identified two miRNAs that target Gab2 to suppress the proliferation and migration of hepatocellular carcinoma (HCC) cells. First, we predicted Gab2-targeting miRNAs through biological websites, and we selected nine miRNAs that were reported in the literature as being abnormally expressed in liver cancer and fatty liver tissue. Then, we measured the expression of these miRNAs in the hepatic epithelial cell line HL-7702 and the HCC cell line HepG2. The expression levels of miR-9, miR-181a, miR-181c, miR-34a, and miR-134 were high in HL-7702 cells but low in HepG2 cells, and their expression patterns were the opposite of Gab2 in these cells. Furthermore, we transfected miR-9, miR-34a, miR-181a, and miR-181c mimics into HepG2 cells and found that only miR-9 and miR-181a reduced the level of Gab2 proteins. miR-9 also reduced the Gab2 mRNA level, but miR-181a did not affect the Gab2 mRNA levels. Using a miRNA-Gab2 3′UTR binding reporter, we confirmed that miR-9 and miR-181a bind to the Gab2 3′UTR region. Finally, we introduced miR-9 and miR-181a mimics into HepG2 cells and found that cell proliferation and migration were significantly inhibited. In conclusion, we identified two novel miRNAs targeting Gab2 and provided potential drug targets for the prevention and treatment of liver cancer.

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FOXD3 and GAB2 as a pair of rivals antagonistically control hepatocellular carcinogenesis

Cited by 2 publications

References 47 publications

Gab2 promotes the growth of colorectal cancer by regulating the M2 polarization of tumor‑associated macrophages

Gab2 promotes the growth of colorectal cancer by regulating the M2 polarization of tumor‑associated macrophages

miR-9 and miR-181a Target Gab2 to Inhibit the Proliferation and Migration of Hepatocellular Carcinoma HepG2 Cells

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