FOXM1/DVL2/Snail axis drives metastasis and chemoresistance of colorectal cancer

Yang, Yuhan; Jiang, Huijie; Li, Wanxin; Chen, Linyi; Zhu, Wanglong; Xian, Yu; Han, Zhengyu; Yin, Liangyu; Liu, Yao; Wang, Yi; Pan, Kehou; Zhang, Kun

doi:10.18632/aging.202300

Cited by 17 publications

(8 citation statements)

References 77 publications

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“…Our results revealed that DYNLT3 is involved in EMT via suppression of Ncadherin, vimentin, Snail, SOX2, and OCT4, and upregulation of E-cadherin expression. chemoresistance in colorectal cancer cells (32,33). However, there is no report on the relationship between Dvl2 and cervical cancer.…”

Section: Discussionmentioning

confidence: 99%

DYNLT3 overexpression induces apoptosis and inhibits cell growth and migration via inhibition of the Wnt pathway and EMT in cervical cancer

et al. 2022

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The role of the dynein light chain Tctex-type 3 (DYNLT3) protein in the biological behavior of cervical cancer and its relative molecular mechanisms were investigated. Immunohistochemical staining was used to detect DYNLT3 protein expression in cervical cancer tissues. Cell proliferation and apoptosis rates and invasiveness and migratory capacities were determined by CCK-8 assays, BrdU staining assays and colony formation assays, fluorescence activated cell sorting (FACS), wound healing assays, and Transwell invasion assays of cervical cancer cells after DYNLT3 modulation. The expression levels of Wnt signaling pathway- and EMT-related proteins were examined by Western blotting. Furthermore, the effects of DYNLT3 on the tumorigenicity and metastasis of cervical cancer in nude mice were analyzed by performing immunohistochemistry, and we found that the expression level of the DYNLT3 protein was higher in human normal cervical tissues than in cervical cancer tissues. Overexpression of DYNLT3 obviously attenuated the proliferation, migration and invasion of CaSki and SiHa cells, and promoted cell apoptosis. Upregulation of DYNLT3 expression markedly decreased the expression of Wnt signaling pathway-related proteins (Dvl2, Dvl3, p-LRP6, Wnt3a, Wnt5a/b, Naked1, Naked2, β-catenin and C-Myc) and EMT-related proteins (N-cadherin, SOX2, OCT4, vimentin and Snail), and increased the expression of E-cadherin and Axin1. However, the opposite results were observed after down-regulation of DYNLT3 expression. Up-regulation of DYNLT3 expression significantly inhibited tumor growth in a nude mouse model, while downregulation of DYNLT3 showed the opposite results. In addition, the major metastatic site of cervical cancer cells in mice was the lung, and downregulation of DYNLT3 expression increased cancer metastasis in vivo. DYNLT3 exerted inhibitory effects on cervical cancer by inhibiting cell proliferation, migration and invasion, promoting cell apoptosis in vitro, and inhibiting tumor growth and metastasis in vivo, possibly by suppressing the Wnt signaling pathway and the EMT.

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Section: Discussionmentioning

confidence: 99%

DYNLT3 overexpression induces apoptosis and inhibits cell growth and migration via inhibition of the Wnt pathway and EMT in cervical cancer

et al. 2022

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“…CAV1 can affect the occurrence and development of CRC through different mechanisms, including via activation of SLC2A3/GLUT3 transcription ( Ha and Chi, 2012 ), suppressing phosphorylation of epidermal growth factor receptor ( Yang et al, 2018 ), and stimulating HMGA1-mediated GLUT3 transcription ( Ha et al, 2012 ). FOXM1, a member of FOX superfamily, has been implicated in CRC progression and chemoresistance ( Varghese et al, 2019 ; Yang et al, 2019 ; Yang et al, 2020 ). Yang et al ( Yang et al, 2019 ) revealed that FOXM1 expression significantly elavated in CRC tissues and was positively linked to tumor size, TNM stage, lymphatic and distant metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…Varghese et al ( Varghese et al, 2019 ) showed that FOXM1 regulates 5-FU resistance in CRC by regulating TYMS expression. Yang et al ( Yang et al, 2020 ) FOXM1 simultaneously promote migration, invasion, and drug resistance of CRC cells through upregulating Snail. MAD2L1, as a member of the spindle checkpoint functional complex, plays a crucial role in cell cycle regulation ( Zhong et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Exploring the Relationship Between Senescence and Colorectal Cancer in Prognosis, Immunity, and Treatment

et al. 2022

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Background: Senescence, as an effective barrier against tumorigenesis, plays a critical role in cancer therapy. However, the role of senescence in colorectal cancer (CRC) has not yet been reported. This study aimed to build a prognostic signature for the prognosis of patients with CRC based on senescence-related genes.Methods: A prognostic signature was built from TCGA based on differentially expressed senescence-related genes by the least absolute shrinkage and selection operator (LASSO) and Cox regression analyses, which were further validated using two Gene Expression Omnibus (GEO) cohorts. The CIBERSORT and ssGSEA algorithms were utilized to analyze the infiltrating abundance of immune cells. The relationship of signature with the immune therapy and the sensitivity of different therapies was explored.Results: We found 93 genes associated with senescence that were differentially expressed. Based on expression and clinical parameters, we developed a senescence-related prognostic signature and its effectiveness was verified using two external validation cohorts. Overall survival was predicted using a prognostic nomogram that incorporated the predictive values of the risk score and clinical traits. Additionally, the risk score was significantly correlated with immune cells infiltration, tumor immune microenvironment (TME) score, immune checkpoints, immunotherapeutic efficacy, and chemotherapy sensitivity.Conclusion: The senescence-related prognostic model can well predict the prognosis, immunotherapeutic response, and identify potential drug targets, which can help guide individualized treatment.

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“…The procedures for western blot analysis and protein visualization were performed according to our previous studies 52 , 54 . Primary antibodies included anti-Mettl3 (ab195352, Abcam), anti-LDHA (ABN311 - EMD Millipore), and anti-YTHDF1 (ab99080, Abcam).…”

Section: Methodsmentioning

confidence: 99%

N⁶-methyladenosine-mediated LDHA induction potentiates chemoresistance of colorectal cancer cells through metabolic reprogramming

Zhang

Yang

et al. 2022

Theranostics

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Background: Chemoresistance to 5-fluorouracil (5-FU) is a major barrier to influence the treatment efficiency of colorectal cancer (CRC) patients, while the precise molecular mechanisms underlying 5-FU resistance remain to be fully elucidated. Methods: The metabolic profiles including ATP generation, glucose consumption, lactate generation, and oxygen consumption rate (OCR) in 5-FU resistant CRC cells were compared with those in their parental cells. Subsequently, a series of in vitro and in vivo experiments were carried out to investigate the mechanisms responsible for metabolic reprogramming of 5-FU resistant CRC cells. Results: We found that 5-FU resistant CRC cells showed increased levels of ATP generation, glucose consumption, lactate generation, and OCR as compared with those in their parental cells. Further, increased levels of mRNA N 6 -methyladenosine (m 6 A) and methyltransferase-like 3 (METTL3) were observed in 5-FU resistant CRC cells. Inhibition or knockdown of METTL3 can suppress glycolysis and restore chemosensitivity of 5-FU resistant CRC cells. Mechanistically, METTL3 enhances the expression of LDHA, which catalyzes the conversion of pyruvate to lactate, to trigger glycolysis and 5-FU resistance. METTL3 can increase the transcription of LDHA via stabilizing mRNA of hypoxia-inducible factor (HIF-1α), further, METTL3 also triggers the translation of LDHA mRNA via methylation of its CDS region and recruitment of YTH domain-containing family protein 1 (YTHDF1). Targeted inhibition of METTL3/LDHA axis can significantly increase the in vitro and in vivo 5-FU sensitivity of CRC cells. Conclusion: Our study indicates that METTL3/LDHA axis-induced glucose metabolism is a potential therapy target to overcome 5-FU resistance in CRC cells.

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FOXM1/DVL2/Snail axis drives metastasis and chemoresistance of colorectal cancer

Cited by 17 publications

References 77 publications

DYNLT3 overexpression induces apoptosis and inhibits cell growth and migration via inhibition of the Wnt pathway and EMT in cervical cancer

DYNLT3 overexpression induces apoptosis and inhibits cell growth and migration via inhibition of the Wnt pathway and EMT in cervical cancer

Exploring the Relationship Between Senescence and Colorectal Cancer in Prognosis, Immunity, and Treatment

N⁶-methyladenosine-mediated LDHA induction potentiates chemoresistance of colorectal cancer cells through metabolic reprogramming

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FOXM1/DVL2/Snail axis drives metastasis and chemoresistance of colorectal cancer

Cited by 17 publications

References 77 publications

DYNLT3 overexpression induces apoptosis and inhibits cell growth and migration via inhibition of the Wnt pathway and EMT in cervical cancer

DYNLT3 overexpression induces apoptosis and inhibits cell growth and migration via inhibition of the Wnt pathway and EMT in cervical cancer

Exploring the Relationship Between Senescence and Colorectal Cancer in Prognosis, Immunity, and Treatment

N6-methyladenosine-mediated LDHA induction potentiates chemoresistance of colorectal cancer cells through metabolic reprogramming

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N⁶-methyladenosine-mediated LDHA induction potentiates chemoresistance of colorectal cancer cells through metabolic reprogramming