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    HIF-1α Affects the Neural Stem Cell Differentiation of Human Induced Pluripotent Stem Cells via MFN2-Mediated Wnt/β-Catenin Signaling. Cui Peng,Zhang Ping,Yuan Lin,Wang Li,Guo Xin,Cui Guanghui,Zhang Yanmin,Li Minghua,Zhang Xiaowei,Li Xiaoqiang,Yin Yuxin,Yu Zhendong Frontiers in cell and developmental biology Hypoxia-inducible factor 1α (HIF-1α) plays pivotal roles in maintaining pluripotency, and the developmental potential of pluripotent stem cells (PSCs). However, the mechanisms underlying HIF-1α regulation of neural stem cell (NSC) differentiation of human induced pluripotent stem cells (hiPSCs) remains unclear. In this study, we demonstrated that HIF-1α knockdown significantly inhibits the pluripotency and self-renewal potential of hiPSCs. We further uncovered that the disruption of HIF-1α promotes the NSC differentiation and development potential and . Mechanistically, HIF-1α knockdown significantly enhances mitofusin2 (MFN2)-mediated Wnt/β-catenin signaling, and excessive mitochondrial fusion could also promote the NSC differentiation potential of hiPSCs via activating the β-catenin signaling. Additionally, MFN2 significantly reverses the effects of HIF-1α overexpression on the NSC differentiation potential and β-catenin activity of hiPSCs. Furthermore, Wnt/β-catenin signaling inhibition could also reverse the effects of HIF-1α knockdown on the NSC differentiation potential of hiPSCs. This study provided a novel strategy for improving the directed differentiation efficiency of functional NSCs. These findings are important for the development of potential clinical interventions for neurological diseases caused by metabolic disorders. 10.3389/fcell.2021.671704
    Mitochondrial matrix protein C14orf159 attenuates colorectal cancer metastasis by suppressing Wnt/β-catenin signalling. British journal of cancer BACKGROUND:The mechanisms underlying metastasis of colorectal cancer (CRC) remain unclear. C14orf159 is a mitochondrial matrix protein converting D-glutamate to 5-oxo-D-proline. Other metabolic functions of C14orf159, especially on mitochondrial metabolism, and its contribution to CRC metastasis, are not elucidated. METHODS:Metabolome analysis by gas chromatography-mass spectrometry, RNA-sequencing analysis, flow cytometry, migration and invasion assay, sphere-formation assay using C14orf159-knockout and -stable expressing cells, immunohistochemistry of C14orf159 in human CRC specimens, and xenograft experiments using Balb/c nude mice were conducted. RESULTS:C14orf159 maintained the mitochondrial membrane potential of human CRC cells, and its involvement in amino acid and glutathione metabolism was demonstrated. In human CRC specimens, a decrease in C14orf159 expression at the invasive front of the tumour and in metastasis was determined. C14orf159 was also shown to attenuate the migration, invasion, and spheroid growth of CRC cells in vitro and colorectal tumour growth and metastasis in vivo. Mechanistically, C14orf159 reduced the expression of genes involved in CRC metastasis, including members of the Wnt and MMP family, by maintaining the mitochondrial membrane potential. CONCLUSIONS:Our findings link mitochondrial membrane potential to Wnt/β-catenin signalling and reveal a previously unrecognised function of the mitochondrial matrix protein C14orf159 as a suppressor of CRC metastasis. 10.1038/s41416-021-01582-9
    HIF-1-regulated expression of calreticulin promotes breast tumorigenesis and progression through Wnt/β-catenin pathway activation. Proceedings of the National Academy of Sciences of the United States of America Calreticulin (CALR) is a multifunctional protein that participates in various cellular processes, which include calcium homeostasis, cell adhesion, protein folding, and cancer progression. However, the role of CALR in breast cancer (BC) is unclear. Here, we report that CALR is overexpressed in BC compared with normal tissue, and its expression is correlated with patient mortality and stemness indices. CALR expression was increased in mammosphere cultures, CD24CD44 cells, and aldehyde dehydrogenase-expressing cells, which are enriched for breast cancer stem cells (BCSCs). Additionally, CALR knockdown led to BCSC depletion, which impaired tumor initiation and metastasis and enhanced chemosensitivity in vivo. Chromatin immunoprecipitation and reporter assays revealed that hypoxia-inducible factor 1 (HIF-1) directly activated transcription in hypoxic BC cells. CALR expression was correlated with Wnt/β-catenin pathway activation, and an activator of Wnt/β-catenin signaling abrogated the inhibitory effect of CALR knockdown on mammosphere formation. Taken together, our results demonstrate that CALR facilitates BC progression by promoting the BCSC phenotype through Wnt/β-catenin signaling in an HIF-1-dependent manner and suggest that CALR may represent a target for BC therapy. 10.1073/pnas.2109144118
    HIF-1α stimulates the progression of oesophageal squamous cell carcinoma by activating the Wnt/β-catenin signalling pathway. British journal of cancer BACKGROUND:This study aimed to clarify the significance of the crosstalk between hypoxia-inducible factor-1α (HIF-1α) and the Wnt/β-catenin pathway in oesophageal squamous cell carcinoma (ESCC). METHODS:The oncogenic role of HIF-1α in ESCC was investigated using in vitro and in vivo assays. The clinicopathological significance of HIF-1α, β-catenin and TCF4/TCF7L2 in ESCC were evaluated using quantitative real-time PCR and immunohistochemistry. RESULTS:The expression level of HIF-1α, β-catenin, and TCF4/TCF7L2 in T.Tn and TE1 cell lines were elevated under hypoxia in vitro. HIF-1α knockdown suppressed proliferation, migration/invasion and epithelial-mesenchymal transition (EMT) progression, induced G0/G1 cell cycle arrest, promoted apoptosis and inhibited 5-fluorouracil chemoresistance in vitro. In vivo assays showed that HIF-1α is essential in maintaining tumour growth, angiogenesis, and 5-fluorouracil chemoresistance. Mechanically, we identified the complex between HIF-1α and β-catenin, HIF-1α can directly bind to the promoter region of TCF4/TCF7L2. The mRNA level of HIF-1α, β-catenin and TCF4/TCF7L2 were increased in ESCC tumour tissues compared to the corresponding non-tumour tissues. High levels of HIF-1α and TCF4/TCF7L2 expression were correlated with aggressive phenotypes and poor prognosis in ESCC patients. CONCLUSIONS:HIF-1α serves as an oncogenic transcriptional factor in ESCC, probably by directly targeting TCF4/TCF7L2 and activating the Wnt/β-catenin pathway. 10.1038/s41416-022-01825-3