• Hypoxia
• Hypoxia inducible factors
• Metastasis
• Non-canonical Wnt signaling
• ROR1/ROR2 co-receptors

• Receptor Tyrosine Kinase-like Orphan Receptors/genetics
• Receptor Tyrosine Kinase-like Orphan Receptors/metabolism
• Humans
• Colonic Neoplasms/pathology
• Colonic Neoplasms/genetics
• Colonic Neoplasms/metabolism
• Animals
• Mice
• Gene Expression Regulation, Neoplastic
• Hypoxia-Inducible Factor 1, alpha Subunit/genetics
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Cell Line, Tumor
• Cell Movement/genetics
• Wnt Signaling Pathway
• Cell Hypoxia
• Cell Proliferation
• Basic Helix-Loop-Helix Transcription Factors/genetics
• Basic Helix-Loop-Helix Transcription Factors/metabolism
• Mice, Nude

• HIF‐3α
• colorectal cancer
• hypoxia
• hypoxia inducible factors

• Humans
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/mortality
• Gene Expression Regulation, Neoplastic
• Basic Helix-Loop-Helix Transcription Factors/genetics
• Basic Helix-Loop-Helix Transcription Factors/metabolism
• Apoptosis/genetics
• Phenotype
• Hypoxia-Inducible Factor 1, alpha Subunit/genetics
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Cell Line, Tumor
• Cell Proliferation
• Prognosis
• Tumor Microenvironment/genetics
• Autophagy
• Repressor Proteins
• Apoptosis Regulatory Proteins

• IN229420 Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México
• IN230323 Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México
• IV200220 Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México
• Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México

• Astragali Radix
• Cancer stemness
• Colorectal cancer
• Curcumae Rhizoma
• HIF-2α
• WNT/β-catenin

• Animals
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/pathology
• beta Catenin/metabolism
• Astragalus propinquus/chemistry
• Mice, Inbred BALB C
• Drugs, Chinese Herbal/pharmacology
• Cell Line, Tumor
• Mice
• Basic Helix-Loop-Helix Transcription Factors/metabolism
• Humans
• Neoplastic Stem Cells/drug effects
• Epithelial-Mesenchymal Transition/drug effects
• Cell Movement/drug effects
• Rhizome/chemistry
• Antineoplastic Agents, Phytogenic/pharmacology
• Wnt Signaling Pathway/drug effects

• M36 inhibitor
• MAPK signaling pathway
• PI3K/Akt/mTOR signaling pathway
• colon cancer
• cytostatic effects
• mitochondrial damage
• mitochondrial dynamics
• p32/gC1qR/C1QBP/HABP1

• DGAPA/UNAM IV200-220 Universidad Nacional Autonoma de Mexico
• DGAPAUNAM IN229420 Universidad Nacional AUuónoma de México

• CD44 isoforms
• HT-29
• colorectal cancer
• metastasis

• Humans
• Heterografts
• Cell Line, Tumor
• Angiogenesis
• Protein Isoforms/genetics
• Protein Isoforms/metabolism
• Colorectal Neoplasms/pathology
• Epithelial-Mesenchymal Transition/genetics
• Hyaluronan Receptors/genetics
• Hyaluronan Receptors/metabolism
• Hypoxia/genetics
• Gene Expression Regulation, Neoplastic

• CE140100003 Australian Research Council Centre of Excellence for Nanoscale BioPhotonics
• 325043972 German Research Foundation
• ID1196520 National Health and Medical Research Council
• ID2009677 National Health and Medical Research Council
• National Research University Higher School of Economics
• Australian Research Council Centre of Excellence for Nanoscale BioPhotonics
• German Research Foundation
• National Health and Medical Research Council
• National Research University Higher School of Economics

• Cancer stemness
• Chinese medicine
• Hepatocellular carcinoma
• Hypoxia
• Jiedu Recipe
• Wnt/β-catenin pathway

• Animals
• Mice
• Humans
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/genetics
• beta Catenin/genetics
• beta Catenin/metabolism
• beta Catenin/pharmacology
• Liver Neoplasms/drug therapy
• Liver Neoplasms/genetics
• Drugs, Chinese Herbal/pharmacology
• Drugs, Chinese Herbal/therapeutic use
• RNA, Messenger/therapeutic use
• Cell Line, Tumor
• Cell Proliferation
• Cell Movement
• Gene Expression Regulation, Neoplastic

Astrin/SPAG5 is a mitotic spindle protein found to be overexpressed in several human cancers, functioning as an oncogene. The expression of Astrin has not been reported so far in colon cancer, nor has it been related to HIFs expression or action. Since mTOR, Astrin, and hypoxia-inducible factors (HIFs) are involved in promoting the growth and survival of cancer cells, we investigated the possible interaction between them in cultured colon cancer cells. Both Astrin and HIF-1α and HIF-2α protein levels were found only expressed in colon cancer cells compared with nonmalignant cells. Our data indicate that mTOR stimulates both Astrin and HIFs expression, but notably, mTORC activity seems to be independent of Astrin expression levels. However, while HIF-1α or HIF-2α stable knockdown increased Astrin expression, mTOR activity was affected in an opposite way by HIF-1α or HIF-2α silencing, indicating that HIF-1α inhibits mTOR while HIF-2α stimulates its activity. These data suggest that mTOR, Astrin, and HIFs compose an integrative network interacting to activate positive or negative regulatory loops probably to coordinate cancer cell growth, metabolism, and survival under oncogenic stress.

•

Colon cancer cells overexpress the mitotic spindle protein Astrin/SPAG5.

• AKT
• CD44
• FOXA2
• breast cancer
• metastasis

• R01 DK108005 NIDDK NIH HHS
• KMU-DK108005, NYTU-KMU-109-IF-01, NYCU-KMU-111-I002, KMU-DK(A)111005 Kaohsiung Medical University, Taiwan
• MOST110-2314-B-037-129, MOST110-2314-B-037-084, MOST110-2314-B-037-058 Ministry of Science and Technology and Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B) from the Featured Areas Research Center Program within the framework of Higher Education Sprout Project by the Ministry of Education, Taiwan
• KMUH110-0R43, KMUH-DK(A)110001 Kaohsiung Medical University Hospital, Taiwan

Molecular oxygen (O₂) is essential for most biological reactions in mammalian cells. When the intracellular oxygen content decreases, it is called hypoxia. The process of hypoxia is linked to several biological processes, including pathogenic microbe infection, metabolic adaptation, cancer, acute and chronic diseases, and other stress responses. The mechanism underlying cells respond to oxygen changes to mediate subsequent signal response is the central question during hypoxia. Hypoxia-inducible factors (HIFs) sense hypoxia to regulate the expressions of a series of downstream genes expression, which participate in multiple processes including cell metabolism, cell growth/death, cell proliferation, glycolysis, immune response, microbe infection, tumorigenesis, and metastasis. Importantly, hypoxia signaling also interacts with other cellular pathways, such as phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) signaling, nuclear factor kappa-B (NF-κB) pathway, extracellular signal-regulated kinases (ERK) signaling, and endoplasmic reticulum (ER) stress. This paper systematically reviews the mechanisms of hypoxia signaling activation, the control of HIF signaling, and the function of HIF signaling in human health and diseases. In addition, the therapeutic targets involved in HIF signaling to balance health and diseases are summarized and highlighted, which would provide novel strategies for the design and development of therapeutic drugs.

• nutrient signalling
• cervical cancer
• hormone receptors

• Acetylglucosamine/metabolism
• Cervix Uteri/metabolism
• Female
• Humans
• Inositol/metabolism
• N-Acetylglucosaminyltransferases/genetics
• Protein Processing, Post-Translational
• Proto-Oncogene Proteins c-akt/metabolism
• Receptor, IGF Type 1/metabolism
• Uterine Cervical Neoplasms/metabolism

Anti-angiogenesis therapy, a promising strategy against cancer progression, is limited by drug-resistance, which could be attributed to changes within the tumor microenvironment. Studies have increasingly shown that combining anti-angiogenesis drugs with immunotherapy synergistically inhibits tumor growth and progression. Combination of anti-angiogenesis therapy and immunotherapy are well-established therapeutic options among solid tumors, such as non-small cell lung cancer, hepatic cell carcinoma, and renal cell carcinoma. However, this combination has achieved an unsatisfactory effect among some tumors, such as breast cancer, glioblastoma, and pancreatic ductal adenocarcinoma. Therefore, resistance to anti-angiogenesis agents, as well as a lack of biomarkers, remains a challenge. In this review, the current anti-angiogenesis therapies and corresponding drug-resistance, the relationship between tumor microenvironment and immunotherapy, and the latest progress on the combination of both therapeutic modalities are discussed. The aim of this review is to discuss whether the combination of anti-angiogenesis therapy and immunotherapy can exert synergistic antitumor effects, which can provide a basis to exploring new targets and developing more advanced strategies.

• antiangiogenic therapy
• cancer biology
• immune therapy
• progress
• tumor microenvironment

• CSCs niche
• cancer stem cells
• targeted therapy
• thyroid cancer
• tumor microenvironment

• CD171)
• colorectal cancer (CRC), organoids, transforming growth factor (TGF)-β signaling, L1 cell adhesion molecule (L1CAM

Angiogenesis belongs to the most clinical characteristics of colorectal cancer (CRC) and is strongly linked to the activation of Wnt/β-catenin signaling. The most prominent factors stimulating constitutive activation of this pathway, and in consequence angiogenesis, are genetic alterations (mainly mutations) concerning APC and the β-catenin encoding gene (CTNNB1), detected in a large majority of CRC patients. Wnt/β-catenin signaling is involved in the basic types of vascularization (sprouting and nonsprouting angiogenesis), vasculogenic mimicry as well as the formation of mosaic vessels. The number of known Wnt/β-catenin signaling components and other pathways interacting with Wnt signaling, regulating angiogenesis, and enabling CRC progression continuously increases. This review summarizes the current knowledge about the role of the Wnt/Fzd/β-catenin signaling pathway in the process of CRC angiogenesis, aiming to improve the understanding of the mechanisms of metastasis as well as improvements in the management of this cancer.

Aberrant activation of the Wnt/Fzd/β-catenin signaling pathway is one of the major molecular mechanisms of colorectal cancer (CRC) development and progression. On the other hand, one of the most common clinical CRC characteristics include high levels of angiogenesis, which is a key event in cancer cell dissemination and distant metastasis. The canonical Wnt/β-catenin downstream signaling regulates the most important pro-angiogenic molecules including vascular endothelial growth factor (VEGF) family members, matrix metalloproteinases (MMPs), and chemokines. Furthermore, mutations of the β-catenin gene associated with nuclear localization of the protein have been mainly detected in microsatellite unstable CRC. Elevated nuclear β-catenin increases the expression of many genes involved in tumor angiogenesis. Factors regulating angiogenesis with the participation of Wnt/β-catenin signaling include different groups of biologically active molecules including Wnt pathway components (e.g., Wnt2, DKK, BCL9 proteins), and non-Wnt pathway factors (e.g., chemoattractant cytokines, enzymatic proteins, and bioactive compounds of plants). Several lines of evidence argue for the use of angiogenesis inhibition in the treatment of CRC. In the context of this paper, components of the Wnt pathway are among the most promising targets for CRC therapy. This review summarizes the current knowledge about the role of the Wnt/Fzd/β-catenin signaling pathway in the process of CRC angiogenesis, aiming to improve the understanding of the mechanisms of metastasis as well as improvements in the management of this cancer.

• Wnt/beta-catenin signaling
• angiogenesis
• anti-angiogenic therapy
• colorectal cancer

Colorectal cancer (CRC) is one of the common causes of cancer death worldwide. Obstructive sleep apnea syndrome (OSAS), sharing many risk factors in common with CRC, is prevalent among CRC patients. OSAS may promote the CRC development independently but the mechanism is still unknown. Intermittent hypoxia (IH) is one of the characteristics of OSAS, and hypoxia may influence the genes associated with CRC. Intestinal microbiota plays important role in CRC carcinogenesis, and OSAS patients have been shown to have intestinal microbiota dysbiosis. We hypothesized that IH and intestinal microbiota dysbiosis may be involved for CRC in patients with OSAS.

We established precancerous cell models of CRC with Immorto-Min colonic epithelial (IMCE) cells. First, the cells were exposed to IH in a special chamber for 4 h, 8 h, and 12 h. Feces from 6 patients with OSAS and 6 healthy controls were collected and made into sterile fecal fluid for incubation with IMCE cells for 12 h. The cells were then exposed to IH for 4 h, 8 h, and 12 h. After IH exposure, the expressions of genes and inflammation cytokines associated with CRC, such as β-catenin, STAT3, HIF-1α, IL-6, TNF-α, c-myc, and cyclinD1, were tested.

IH activated the expression of HIF-1α and STAT3 both in mRNA and protein level (HIF-1α: P = 0.015 for mRNA level, P = 0.027 for protein level; STAT3: P = 0.023 for mRNA level, P = 0.023 for protein level), and promoted p-STAT3 shifting to the nucleus (P = 0.023). The mRNA of β-catenin (P = 0.022) and cyclinD1 (P = 0.023) was elevated, but there was no change for the β-catenin protein in the nucleus. Gut microbiota of OSAS patients promoted the expression of STAT3 (protein level: 0 h: P = 0.037; 4 h: P = 0.046; 8 h: P = 0.049; 12 h: P = 0.037), promoted p-STAT3 (4 h: P = 0.049; 8 h: P = 0.046; 12 h: P = 0.046) shifting to the nucleus, and also elevated the expression of IL-6 and TNF-α in mRNA level at 4 h (IL-6: P = 0.037, TNF-α: P = 0.037) and 8 h (IL-6: P = 0.037, TNF-α: P = 0.037). The protein of β-catenin in the nucleus was not affected by IH and gut microbiota from OSAS.

Our study demonstrated that IH and gut microbiota of patients with OSAS activated HIF-1α expression and STAT3 pathway in IMCE cells, with no influence on β-catenin pathway, which suggested that IH, STAT3 pathway, chronic inflammation, and intestinal microbiota dysbiosis may be involved in CRC carcinogenesis correlated with OSAS These findings must be interpreted cautiously and further research is necessary to clarify the causative steps in CRC development.

• Colorectal cancer
• Intermittent hypoxia
• Intestinal microbiota
• Obstructive sleep apnea syndrome

• Cell Culture Techniques
• Cell Line
• Colorectal Neoplasms/genetics
• Feces/microbiology
• Gastrointestinal Microbiome
• Humans
• Hypoxia/physiopathology
• Sleep Apnea, Obstructive/microbiology
• Sleep Apnea, Obstructive/physiopathology

• National Natural Science Foundation of China

TC10-like (TCL) is a small GTPase that has been implicated in carcinogenesis. Elevated TCL expression has been observed in many different types of cancers although the underlying epigenetic mechanism is poorly understood. Here we report that TCL up-regulation was associated with high malignancy in both human colorectal cancer biopsy specimens and in cultured colorectal cancer cells. Hypoxia, a pro-metastatic stimulus, up-regulated TCL expression in HT-29 cells. Further studies revealed that myocardin-related transcription factor A (MRTF-A) promoted migration and invasion of HT-29 cells in a TCL-dependent manner. MRTF-A directly bound to the proximal TCL promoter in response to hypoxia to activate TCL transcription. Chromatin immunoprecipitation (ChIP) assay showed that hypoxia stimulation specifically enhanced acetylation of histone H4K16 surrounding the TCL promoter, which was abolished by MRTF-A depletion or inhibition. Mechanistically, MRTF-A interacted with and recruited the H4K16 acetyltransferase hMOF to the TCL promoter to cooperatively regulate TCL transcription. hMOF depletion or inhibition attenuated hypoxia-induced TCL expression and migration/invasion of HT-29 cells. In conclusion, our data identify a novel MRTF-A-hMOF-TCL axis that contributes to colorectal cancer metastasis.

• Cancer stem cells (CSCs)
• HIF inhibitors
• Hypoxia inducible factors (HIFs)
• Tumor resistance

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Drug Resistance, Neoplasm/drug effects
• Gene Expression Regulation, Neoplastic
• Humans
• Hypoxia/pathology
• Hypoxia-Inducible Factor 1/pharmacology
• Hypoxia-Inducible Factor 1/therapeutic use
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/pathology
• Tumor Microenvironment/drug effects

• B-cell translocation gene 3
• Colorectal cancer
• Hypoxia
• Radiation therapy
• Resistance

The mechanisms by which oligodendroglia modulate CNS angiogenesis remain elusive. Previous in vitro data suggest that oligodendroglia regulate CNS endothelial cell proliferation and blood vessel formation through hypoxia inducible factor alpha (HIFα)-activated Wnt (but not VEGF) signaling. Using in vivo genetic models, we show that HIFα in oligodendroglia is necessary and sufficient for angiogenesis independent of CNS regions. At the molecular level, HIFα stabilization in oligodendroglia does not perturb Wnt signaling but rather activates VEGF. At the functional level, genetically blocking oligodendroglia-derived VEGF but not Wnt significantly decreases oligodendroglial HIFα-regulated CNS angiogenesis. Blocking astroglia-derived Wnt signaling reduces astroglial HIFα-regulated CNS angiogenesis. Together, our in vivo data demonstrate that oligodendroglial HIFα regulates CNS angiogenesis through Wnt-independent and VEGF-dependent signaling. These findings suggest an alternative mechanistic understanding of CNS angiogenesis by postnatal glial cells and unveil a glial cell type-dependent HIFα-Wnt axis in regulating CNS vessel formation.

In the central nervous system, the maturation of glial cells is temporally and functionally coupled with that of the vascular network during postnatal development. Here the authors show that oligodendroglial HIFα regulates CNS angiogenesis through Wnt-independent and VEGF-dependent signaling, while astroglial HIFα participates through Wnt-dependent signaling.

Cancer stem cells play critical roles in tumor initiation, progression, and relapse. Since we previously found that GATA6 promotes the stemness in HCT‐116 and HT‐29 human colorectal cancer (CRC) cells, we aimed to identify the downstream mediator(s) of the stemness‐stimulating effect of GATA6 herein. LRH‐1 was found as a direct target of GATA6 and its upregulation promoted the stemness in both HCT‐116 and HT‐29 cells. Subsequently, hypoxia‐inducible factor‐1α (HIF‐1α) was identified as a direct target of LRH‐1 and its expression level and activity were significantly elevated in the LRH‐1‐overexpressing clones established from the aforementioned two CRC lines. Accordingly, the expression levels of several HIF‐1α targets were also markedly increased, resulting in a stronger glycolysis associated with dramatic elevations of the lactate levels in these cells. Strikingly, higher mitochondrial activities were also found in these clones which might be attributed to the increase of PGC‐1α stimulated by the lactate uptaken through the upregulated MCT‐1. Finally, significant increases in the self‐renewal ability, intracellular radical oxygen species levels and mitochondrial mass were detected in the CD133⁺/CD44⁺ subpopulations isolated from CRC cells regardless of their LRH‐1 expression levels. Together, our results suggest a novel metabolic symbiosis between different colorectal cancer stem cell subpopulations critical for maintaining their mutual stemness.

• GATA6
• LRH-1
• colon cancer
• metabolic symbiosis
• stemness

• autophagy
• colon cancer
• drug resistance
• hypoxia-inducible factors

• de México : IN215514 and IN225717 Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma
• FOSSIS 2017-289600 Consejo Nacional de Ciencia y Tecnología

• Colon cancer stem cells
• Colorectal cancer
• Hedgehog pathway
• Notch pathway
• Wnt/beta-catenin pathway

Iron metabolism and tumor biology are intimately linked. Iron facilitates the production of oxygen radicals, which may either result in iron-induced cell death, ferroptosis, or contribute to mutagenicity and malignant transformation. Once transformed, malignant cells require high amounts of iron for proliferation. In addition, iron has multiple regulatory effects on the immune system, thus affecting tumor surveillance by immune cells. For these reasons, inconsiderate iron supplementation in cancer patients has the potential of worsening disease course and outcome. On the other hand, chronic immune activation in the setting of malignancy alters systemic iron homeostasis and directs iron fluxes into myeloid cells. While this response aims at withdrawing iron from tumor cells, it may impair the effector functions of tumor-associated macrophages and will result in iron-restricted erythropoiesis and the development of anemia, subsequently. This review summarizes our current knowledge of the interconnections of iron homeostasis with cancer biology, discusses current clinical controversies in the treatment of anemia of cancer and focuses on the potential roles of iron in the solid tumor microenvironment, also speculating on yet unknown molecular mechanisms.

• ACD
• TAM
• anemia of cancer
• ferroptosis
• hepcidin
• iron

• Colorectal cancer
• Gene therapy
• Immunotherapy
• Signaling
• Targeted therapy

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Carcinogenesis/drug effects
• Carcinogenesis/genetics
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/immunology
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/therapy
• Genetic Therapy/methods
• Humans
• Immunotherapy/methods
• Molecular Targeted Therapy/methods
• Mutation
• Oncogenes/drug effects
• Oncogenes/genetics
• Oncolytic Virotherapy/methods
• Signal Transduction/drug effects
• Signal Transduction/immunology
• Tumor Suppressor Proteins/genetics
• Tumor Suppressor Proteins/metabolism

• CRC
• EMT
• hypoxia
• metastasis
• miRNA675

• CD44
• EMT
• apoptosis resistance
• cancer initiating cells
• metastasis
• migration
• tumor exosomes

• EMT
• colorectal cancer
• metastasis

• Cancer
• GTPases
• Metastasis
• Rac
• Rho

• Achaete scute-like 2
• Colorectal cancer
• Epithelial-mesenchymal transition
• Hypoxia
• Hypoxia inducible factor-1α
• miRNA-200b

Pancreatic cancer is a devastating disease that is characterized by persistent hypoxia. The roles of hypoxia-inducible factor-2α (hif-2α) are different to those of hif-1α, although both are critical for tumor cells to adapt to the hypoxic microenvironment. However, unlike the well-studied hif-1α, the role of hif-2α in tumors, including pancreatic cancer, is poorly understood.

Herein, we used a mutated hif-2α (A530T) to figure out the problem that wild-type hif-2α is quickly degraded which limits the study of its function. Using several cell lines, mouse models, and human tissues, we obtained a general picture of hif-2α in pancreatic cancer progression.

Functional assays revealed that hif-2α promotes epithelial-to-mesenchymal transition, enhances tumor proliferation and invasion, increases stemness, facilitates angiogenesis, and up-regulates aerobic glycolysis. We identified an interaction between hif-2α and β-catenin, and found that hif-2α/β-catenin complex formation increased the activity of β-catenin and the protein stability of hif-2α. In vivo study confirmed the pro-oncogenic role of hif-2α, whose expression correlated with those of E-cadherin, vimentin, Ki-67, and CD31, but not hif-1α. A human tissue study showed that hif-2α was associated with lymph node metastasis, pathological grade, stroma abundance, vascularization and patient survival. High expression of hif-2α was also identified as an independent indicator of poor prognosis in patients with pancreatic cancer.

Our systematic study revealed the roles of hif-2α in pancreatic cancer, and may provide a novel target for this highly malignant disease.

• Cancer stem cell
• EPAS1
• Metabolic shift
• PDAC
• Protein interaction

• CD44
• Computational modeling
• Epithelial to mesenchymal transition
• Glioma

• Breast cancer
• aldehyde dehydrogenase 1 (ALDH1)
• cancer stem cell (CSC)
• therapy resistance

Mesenchymal stem/stromal cells (MSCs) reside in the bone marrow and maintain their stemness under hypoxic conditions. However, the mechanism underlying the effects of hypoxia on MSCs remains to be elucidated. This study attempted to uncover the signaling pathway of MSC proliferation. Under low-oxygen culture conditions, MSCs maintained their proliferation and differentiation abilities for a long term. The Notch2 receptor was up-regulated in MSCs under hypoxic conditions. Notch2-knockdown (Notch2-KD) MSCs lost their cellular proliferation ability and showed reduced gene expression of hypoxia-inducible transcription factor (HIF)-1α, HIF-2α, and c-Myc. Overexpression of the c-Myc gene in Notch2-KD MSCs allowed the cells to regain their proliferation capacity. These results suggested that Notch2 signaling is linked to c-Myc expression and plays a key role in the regulation of MSC proliferation. Our findings provide important knowledge for elucidating the self-replication competence of MSCs in the bone marrow microenvironment.

• Animals
• Bone Marrow/metabolism
• Cell Differentiation
• Cell Hypoxia
• Cell Proliferation
• Cells, Cultured
• Female
• Gene Expression Regulation
• Genes, myc
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Mice
• Receptor, Notch2/metabolism
• Signal Transduction

• Japanese Association for Acute Medicine
• The grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan

• Animals
• Cell Line, Tumor
• Drug Resistance, Neoplasm/drug effects
• Drug Resistance, Neoplasm/physiology
• Gastrointestinal Neoplasms/drug therapy
• Gastrointestinal Neoplasms/metabolism
• Humans
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/metabolism
• Reactive Oxygen Species/metabolism
• Signal Transduction/drug effects

The role of Achaete scute-like 2 (Ascl2) in colorectal cancer (CRC) cell differentiation is unknown. LS174T, HT-29 and Caco-2 cells have high Ascl2 expression, while Lovo and SW480 cells have low Ascl2 expression. LS174T and HT-29 cells with Ascl2 knockdown were transfected with caudal type homeobox 2 (CDX2) promoter constructs and used for luciferase assays and chromatin immunoprecipitation (ChIP) assays. Ascl2 knockdown promoted differentiation of CRC cells into a goblet cell phenotype, as determined by increased expression of MUC2, TFF3, and CDX2. Ascl2 knockdown activated CDX2 expression through a transcriptional mechanism via direct binding of Ascl2 to the proximal E-box of the CDX2 promoter. Ascl2 over-expression in Lovo and SW480 cells inhibited a goblet cell phenotype, as determined by reduced CDX2 and MUC2 expression. Inverse correlations between Ascl2 and CDX2, and Ascl2 and MUC2 mRNA levels, as well as Ascl2 and CDX2 protein levels were observed in CRC cancerous samples. This study demonstrates CDX2 repression by Ascl2 and highlights a role for Ascl2 in CRC cell differentiation. These findings suggest that the Ascl2/CDX2 axis may serve as a potential therapeutic target in colorectal cancer.

• Achaete scute-like 2
• CDX2
• colorectal carcinoma
• differentiation
• transcriptional regulation

• cancer development and progression
• cancer stem cell
• carcinogenesis
• long noncoding RNA

Cluster of differentiation 44 (CD44) is a transmembrane glycoprotein that serves as the receptor for the extracellular matrix component hyaluronic acid. CD44 has been reported to play key roles in cell proliferation, motility, and survival, but its role in breast cancer remains controversial. In this study, we conducted a meta-analysis. A total of 23 published Gene Expression Omnibus databases were included to evaluate the association between CD44 mRNA expression and clinicopathological characteristics or prognosis of the patients with breast cancer. Our analysis revealed that CD44 expression was associated with clinicopathological features, including the histological grade, estrogen receptor status, progesterone receptor status, and human epidermal growth factor receptor-2 status. Higher levels of CD44 expression were observed in the basal subtype of breast cancer both at the mRNA and protein levels (odds ratio [OR] =2.08, 95% confidence interval [CI]: 1.72–2.52; OR =2.11, 95% CI: 1.67–2.68). Patients with CD44 overexpression exhibited significantly worse overall survival (hazard ratio =1.27; 95% CI: 1.04–1.55). Whole gene profile analysis revealed that CD44 expression was enriched in basal-type breast cancer and correlated with epithelial–mesenchymal transition and cancer stem cell gene profiles. In summary, our analyses indicated that CD44 potentially might be a prognostic marker for breast cancer and thus can serve as a therapeutic target for basal-type breast cancer.

• CD44
• biomarker
• breast cancer
• meta-analysis
• survival prediction

• Wnt signaling
• developmental biology
• hypoxia
• stem cells
• zebrafish

CD44, a multi-structural and multifunctional transmembrane glycoprotein, was initially identified as a receptor for hyaluronan that participates in both physiological and pathological processes. CD44 is found to be closely linked to the development of various solid tumors. Molecular studies have revealed that high CD44 expression was correlated with the phenotypes of cancer stem cells and epithelial–mesenchymal transition, thereby contributing to tumor invasion, metastasis, recurrence, and chemoresistance. Correspondingly, blockade of CD44 has been demonstrated to be capable of attenuating the malignant phenotype, slowing cancer progression, and reversing therapy resistance. Clinical analyses showed that high CD44 expression is associated with poor survival of various cancer patients, indicating that CD44 can be a potential prognostic marker. In this review, we summarize recent research progress of CD44 on tumor biology and the clinical significance of CD44.

• CD44
• epithelial–mesenchymal transition
• prognosis
• tumor progression

• Dietary agents
• cancer stem cells
• mechanism of action
• review
• signal transduction pathways

• Antineoplastic Agents/pharmacology
• Biological Products/pharmacology
• Humans
• Neoplasms/pathology
• Neoplasms/prevention & control
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/pathology
• Prognosis

• R01CA138797 NCI NIH HHS
• R01 CA138797 NCI NIH HHS
• R01CA140605 NCI NIH HHS
• R01 AT002890 NCCIH NIH HHS
• R01 CA185972 NCI NIH HHS
• R01 CA140605 NCI NIH HHS