Abstract. Hypoxia inducible factors (HIFs) are transcription factors, which are commonly expressed in mammals, including humans. The HIFs consist of hypoxia-regulated α and oxygen-insensitive β subunits, and are key regulators of gene expression during hypoxia in normal and solid tumor tissues. Three members of the HIF family, HIF-1α, HIF-2α, and HIF-3α, are currently known. HIF-3α differs from HIF-1α and HIF-2α in protein structure and regulation of gene expression. For a long time, HIF-3α was considered as a negative mediator of HIF-regulated genes. HIF-3 has a transcriptional regulatory function, which negatively affects gene expression by competing with HIF-1α and HIF-2α in binding to transcriptional elements in target genes during hypoxia. Previously, certain target genes of HIF-3α have been identified, confirming the role of HIF-3α as a transcription factor. In this review, the protein structure, gene regulation and biological function of HIF-3 are discussed based on the literature.

Gastrointestinal stromal tumors (GISTs) are the major gastrointestinal mesenchymal tumors with a variable malignancy ranging from a curable disorder to highly malignant sarcomas. Metastasis and recurrence are the main causes of death in GIST patients. To further explore the mechanism of metastasis and to more accurately estimate the recurrence risk of GISTs after surgery, the clinical significance and functional role of collagen triple helix repeat containing-1 (CTHRC1) in GIST were investigated. We found that CTHRC1 expression was gradually elevated as the risk grade of NIH classification increased, and was closely correlated with disease-free survival and overall survival in 412 GIST patients. In vitro experiments showed that recombinant CTHRC1 protein promoted the migration and invasion capacities of primary GIST cells. A luciferase reporter assay and pull down assay demonstrated that recombinant CTHRC1 protein activated noncanonical Wnt/PCP-Rho signaling but inhibited canonical Wnt signaling. The pro-motility effect of CTHRC1 on GIST cells was reversed by using a Wnt5a neutralizing antibody and inhibitors of Rac1 or ROCK. Taken together, these data indicate that CTHRC1 may serve as a new predictor of recurrence risk and prognosis in post-operative GIST patients and may play an important role in facilitating GIST progression. Furthermore, CTHRC1 promotes GIST cell migration and invasion by activating Wnt/PCP-Rho signaling, suggesting that the CTHRC1-Wnt/PCP-Rho axis may be a new therapeutic target for interventions against GIST invasion and metastasis.

[1] West Kunlun Mountains have continuous loess deposits. However, very few papers have explored the rock magnetic characteristics of loess deposited there. Thus, although Kunlun Mountains loess is one of the useful paleoclimate archives, its importance has not been emphasized. Here we present detailed rock magnetic and bulk grain-size studies on a 207 m loess core on the northern slope of the West Kunlun Mountains. We find that magnetic susceptibility of loess from the northern slope of the West Kunlun Mountains is not controlled by changes in the concentration of ultrafine pedogenic magnetite and maghemite, but instead controlled by changes in the concentration of aeolian multidomain magnetite and maghemite. This is unsurprising given the low rainfall of the Kunlun region and the lack of postdepositional weathering and soil formation in these aeolian sequences. In addition, we find that magnetic susceptibility values increase dramatically at 111 m corresponding to an age of ∼0.5 Ma. The magnetic susceptibility increase is accompanied by coarsening of both bulk and magnetic grain size and softening of magnetic mineralogy. We tentatively tie these changes in rock magnetic and grain-size parameter records to an expansion of desert environment.

: Tumor development has been closely linked to tumor microenvironment, particularly in terms of myeloid-derived suppressive cells (MDSCs), a heterogeneous population of immature myeloid cells that protect tumors from elimination by immune cells. Approaches aimed at blocking MDSC accumulation could improve cancer clinical outcome. : We investigated that metformin suppressed MDSC migration to inhibit cancer progression. Primary tumor tissues were incubated with metformin, and proinflammatory chemokine production was measured. To study MDSC chemotaxis, BALB/C nude mice were injected subcutaneously with TE7 cells and treated with metformin. Migration of adoptively transferred MDSCs was analyzed using flow cytometry and immunohistochemistry. : The frequency of tumor-infiltrated polymorphonuclear (PMN)-MDSCs was increased compared to their circulating counterparts. There was a significant correlation between PMN-MDSCs accumulation in tumors and ESCC prognosis. Moreover, PMN-MDSCs displayed immunosuppressive activity. Treatment with metformin reduced MDSC migration in patients. Metformin inhibited CXCL1 secretion in ESCC cells and tumor xenografts by enhancing AMPK phosphorylation and inducing DACH1 expression, leading to NF-κB inhibition and reducing MDSC migration. Knockdown of AMPK and DACH1 expression blocked the effect of metformin on MDSC chemotaxis. : A novel anti-tumor effect of metformin, which is mediated by reducing PMN-MDSC accumulation in the tumor microenvironment via AMPK/DACH1/CXCL1 axis.

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Objective: Cancer is expected to be the leading cause of death worldwide within the 21st century and is the single most important obstacle to extending life expectancy. Unfortunately, the most effective approach to combating cancers remains a complex and unsolved problem. Siglec-15 is a member of the Siglec family and plays a conserved regulatory role in the immune system of vertebrates. Previous studies on Siglec-15 have focused on its function in osteoclast regulation. The purpose of this study was to explore the significance of Siglec-15 mRNA in human cancer mainly based on information obtained from online databases. Method: Data were collected from several online databases. Serial analysis of gene expression (SAGE) and Virtual Northern, UALCAN Database Analysis, Catalog of Somatic Mutations in Cancer (COSMIC) analysis, the cBio cancer genomics portal, Cancer Regulome tools and data, Kaplan-Meier Plotter Analysis and the UCSC Xena website were used to analyze the data. Results: Compared with normal tissues, Siglec-15 up-regulation was widely observed in tuomrs. Differences in Siglec-15 expression were associated with different prognoses. Siglec-15 mutations are widely observed in tumors and interact with different genes in different cancer types. Conclusion: Siglec-15 is a potential target for the expansion of cancer immunotherapy.

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