Inactivation of APC Induces CD34 Upregulation to Promote Epithelial-Mesenchymal Transition and Cancer Stem Cell Traits in Pancreatic Cancer

Hsieh, Mei Jen; Chiu, Tai‐Jan; Lin, Yn-Hwang; Weng, Ching-Chieh; Weng, Yu‐Ting; Hsiao, Chang‐Chun; Cheng, Kuang‐Hung

doi:10.3390/ijms21124473

Cited by 13 publications

(12 citation statements)

References 49 publications

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“…Importantly, we noticed a familiar tumor suppressor gene, APC, among these genes. It was confirmed that APC could inhibit the Wnt signaling pathway, a carcinogenic signaling pathway in several cancers, and the low expression of APC promoted tumor progression ( 45 ). Afterwards, we analyzed and confirmed that there were multiple m6A sites on the APC mRNA via the Whistle database ( Table S2 ).…”

Section: Discussionmentioning

confidence: 95%

Analysis of N6-Methyladenosine Methyltransferase Reveals METTL14 and ZC3H13 as Tumor Suppressor Genes in Breast Cancer

et al. 2020

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ObjectivesRecently, an increasing number of studies have revealed that N6-methyladenosine (m6A) functions as a significant post-transcriptional modification which plays a critical role in the occurrence and progression of enriched tumors by regulating coding and non-coding RNA biogenesis. However, the biological function of m6A in breast cancer remains largely unclear.Materials and MethodsIn this study, we used a series of bioinformatic databases and tools to jointly analyze the expression of m6A methylation transferases (METTL3, METTL14, WTAP, RBM15, RBM15B and ZC3H13) and investigate the prognostic value of METTL14 and ZC3H13 in breast cancer. Besides, we analyzed the downstream carcinogenic molecular mechanisms related to METTL14 and ZC3H13 and their relationship with immune infiltration in breast tumor tissues.ResultsThe results showed that METTL14 and ZC3H13 were the down-regulated m6A methylation transferases in breast cancer. Survival outcome analysis suggested that abnormally low expression of METTL14 and ZC3H13 could predict unfavorable prognosis in four breast cancer subtypes. Moreover, their down-regulation was associated with ER-, PR- and triple-negative breast cancer patients, as well as tumor progression (increased Scarff, Bloom and Richardson grade status and Nottingham Prognostic Index classification). Co-expression analysis revealed that METTL14 and ZC3H13 had a strong positive correlation with APC, an antagonist of the Wnt signaling pathway, indicating they might cooperate in regulating proliferation, invasion, and metastasis of tumor cells. METTL14, ZC3H13, and APC expression levels had significant positive correlation with infiltrating levels of CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells, and negative correlation with Treg cells in breast cancer.ConclusionsThis study demonstrated that down-regulation of METTL14 and ZC3H13 which act as two tumor suppressor genes was found in breast cancer and predicted poor prognosis. Their abnormal expression promoted breast cancer invasion by affecting pathways related to tumor progression and mediating immunosuppression.

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Section: Discussionmentioning

confidence: 95%

Analysis of N6-Methyladenosine Methyltransferase Reveals METTL14 and ZC3H13 as Tumor Suppressor Genes in Breast Cancer

et al. 2020

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“…Importantly, we noticed a familiar tumor suppressor gene, APC, among these genes. It was con rmed that APC could inhibit the Wnt signaling pathway, a carcinogenic signaling pathway in several cancers, and the low expression of APC promoted tumor progression [45]. Afterwards, we analyzed and con rmed that there were multiple m6A sites on the APC mRNA via the Whistle database (Table S1).…”

Section: Discussionmentioning

confidence: 99%

Analysis of N6-methyladenosine (m6A) methyltransferase reveals METTL14 and ZC3H13 as tumor suppressor genes in breast cancer

Gong

Shao

Yang

et al. 2020

Preprint

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Abstract Background Recently, an increasing number of studies have revealed that N6-methyladenosine (m6A) functions as a significant post-transcriptional modification which plays a critical role in the occurrence and progression of enriched tumors by regulating mRNA and non-coding RNA biogenesis. However, the biological function of m6A in breast cancer remains largely unclear. Materials and Methods In this study, we used a serious of bioinformatic databases and tools to jointly analyze the expression of m6A methylation transferases (METTL13, METTL14, WTAP, RBM15, RBM15B and ZC3H13) and investigate the prognostic value of METTL14 and ZC3H13 in breast cancer. Besides, we analyzed the downstream carcinogenic molecular mechanisms related to METTL14 and ZC3H13, and their relationship with immune infiltration in breast tumor tissues. Results The results showed that METTL14 and ZC3H13 were the down-regulated m6A “writers” in breast cancer. Survival outcomes analysis suggested that abnormally low expression of METTL14 and ZC3H13 could predict unfavorable prognosis in four breast cancer subtypes. Moreover, the down-regulation of them was associated with ER-, PR- and basal-like, TNBC patients, as well as tumor progression (increased Scarff, Bloom and Richardson grade status and Nottingham Prognostic Index classification). Co-expression analysis revealed that METTL14 and ZC3H13 had a strong positive correlation with APC, an antagonist of the Wnt signaling pathway, indicating they might cooperate in regulating proliferation, invasion and metastasis of tumor cells. METTL14, ZC3H13 and APC expression levels had significant positive correlation with infiltrating levels of CD4 + T cells, CD8 + T cells, neutrophils, macrophages and Dendritic cells, and negatively with Treg cells in breast cancer. Conclusions This study demonstrated that down-regulation of METTL14 and ZC3H13 which act as two tumor suppressor genes was found in breast cancer and predicted poor prognosis. Their abnormal expression promoted breast cancer invasion by affecting pathways related to tumor progression and mediating immunosuppression.

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“…Protein expression levels from Western blots were quantified using Image J. The expression of all proteins was quantified with respect to the expression of β-actin or GAPDH as previously described [ 8 ]. For cytokine analysis, the RayBio Mouse Cytokine Array C3 (Cat:AAM-CYT-3–4) was purchased from RayBiotech, Inc., Norcross, GA, USA.…”

Section: Methodsmentioning

confidence: 99%

“…Unlike other malignancies, no marked improvement has been achieved in PC survival [ 3 ]. The signature molecular alterations in PC include multiple evolutionary steps of the precursor lesions of which progression involves the acquisition of mutations in Kras, Ink4a, p53, SMAD4, LKB1, APC, or β-catenin [ 4 , 5 , 6 , 7 , 8 ]. Pathology analysis has revealed that PC appears to arise from three distinct precursor lesions that transform the pancreatic ducts: pancreatic intraepithelial neoplasms (PanINs), which are small and focal; intraductal papillary mucinous neoplasms (IPMNs), which are moderate-sized, papillary cystic lesions lined by mucin-producing tall columnar epithelium; and mucinous cystic neoplasms (MCNs), comprising oligomegacysts with a single thin layer of cuboidal and flattened epithelium and associated with an ovarian-type of stroma [ 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of β-Catenin Activity Abolishes LKB1 Loss-Driven Pancreatic Cystadenoma in Mice

Hsieh

Weng

Lin

et al. 2021

IJMS

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Pancreatic cancer (PC) is the seventh leading cause of cancer death worldwide, and remains one of our most recalcitrant and dismal diseases. In contrast to many other malignancies, there has not been a significant improvement in patient survival over the past decade. Despite advances in our understanding of the genetic alterations associated with this disease, an incomplete understanding of the underlying biology and lack of suitable animal models have hampered efforts to develop more effective therapies. LKB1 is a tumor suppressor that functions as a primary upstream kinase of adenine monophosphate-activated protein kinase (AMPK), which is an important mediator in the regulation of cell growth and epithelial polarity pathways. LKB1 is mutated in a significant number of Peutz–Jeghers syndrome (PJS) patients and in a small proportion of sporadic cancers, including PC; however, little is known about how LKB1 loss contributes to PC development. Here, we report that a reduction in Wnt/β-catenin activity is associated with LKB1 tumor-suppressive properties in PC. Remarkably, in vivo functional analyses of β-catenin in the Pdx-1-Cre LKB1L/L β-cateninL/L mouse model compared to LKB1 loss-driven cystadenoma demonstrate that the loss of β-catenin impairs cystadenoma development in the pancreas of Pdx-1Cre LKB1L/L mice and dramatically restores the normal development and functions of the pancreas. This study further determined the in vivo and in vitro therapeutic efficacy of the β-catenin inhibitor FH535 in suppressing LKB1 loss-driven cystadenoma and reducing PC progression that delineates the potential roles of Wnt/β-catenin signaling in PC harboring LKB1 deficiency.

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Inactivation of APC Induces CD34 Upregulation to Promote Epithelial-Mesenchymal Transition and Cancer Stem Cell Traits in Pancreatic Cancer

Cited by 13 publications

References 49 publications

Analysis of N6-Methyladenosine Methyltransferase Reveals METTL14 and ZC3H13 as Tumor Suppressor Genes in Breast Cancer

Analysis of N6-Methyladenosine Methyltransferase Reveals METTL14 and ZC3H13 as Tumor Suppressor Genes in Breast Cancer

Analysis of N6-methyladenosine (m6A) methyltransferase reveals METTL14 and ZC3H13 as tumor suppressor genes in breast cancer

Inhibition of β-Catenin Activity Abolishes LKB1 Loss-Driven Pancreatic Cystadenoma in Mice

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