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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, CD24⁻CD44⁺ 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 CALR 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.

Hypoxia-inducible factors (HIFs) are essential transcription factors that orchestrate cellular responses to oxygen deprivation. HIF-1α, as an unstable subunit of HIF-1, is usually hydroxylated by prolyl hydroxylase domain enzymes under normoxic conditions, leading to ubiquitination and proteasomal degradation, thereby keeping low levels. Instead of hypoxia, sometimes even in normoxia, HIF-1α translocates into the nucleus, dimerizes with HIF-1β to generate HIF-1, and then activates genes involved in adaptive responses such as angiogenesis, metabolic reprogramming, and cellular survival, which presents new challenges and insights into its role in cellular processes. Thus, the review delves into the mechanisms by which HIF-1 maintains its stability under normoxia including but not limited to giving insights into transcriptional, translational, as well as posttranslational regulation to underscore the pivotal role of HIF-1 in cellular adaptation and malignancy. Moreover, HIF-1 is extensively involved in cancer and cardiovascular diseases and potentially serves as a bridge between them. An overview of HIF-1-related drugs that are approved or in clinical trials is summarized, highlighting their potential capacity for targeting HIF-1 in cancer and cardiovascular toxicity related to cancer treatment. The review provides a comprehensive insight into HIF-1’s regulatory mechanism and paves the way for future research and therapeutic development.

The contribution of long noncoding RNAs (lncRNAs) to pancreatic cancer progression and the regulatory mechanisms of their expression are attractive areas. In the present study, the overexpression of lncRNA-BX111887 (BX111) in pancreatic cancer tissues was detected by microarray and further validated in a cohort of pancreatic cancer tissues. We further demonstrated that knockdown or overexpression of BX111 dramatically repressed or enhanced proliferation and invasion of pancreatic cancer cells. Mechanically, BX111 activated transcription of ZEB1, a key regulator for epithelia-mesenchymal transition (EMT), via recruiting transcriptional factor Y-box protein (YB1) to its promoter region. Moreover, we revealed that BX111 transcription was induced by hypoxia-inducible factor (HIF-1α) in response to hypoxia. In addition, BX111 contributed to the hypoxia-induced EMT of pancreatic cells by regulating expression of ZEB1 and its downstream proteins E-cadherin and MMP2. Coincidence with in vitro results, BX111 depletion effectively inhibited growth and metastasis of xenograft tumor in vivo. The clinical samples of pancreatic cancer further confirmed a positive association between BX111 and ZEB1. Moreover, high BX111 expression was correlated with late TNM stage, lymphatic invasion and distant metastasis, as well as short overall survival time in patients. Taken together, our findings implicate a hypoxia-induced lncRNA contributes to metastasis and progression of pancreatic cancer, and suggest BX111 might be applied as a potential biomarker and therapeutic target for pancreatic cancer.

Mitochondria are essential cellular organelles that are involved in regulating cellular energy, metabolism, survival, and proliferation. To some extent, cancer is a genetic and metabolic disease that is closely associated with mitochondrial dysfunction. Hypoxia-inducible factors (HIFs), which are major molecules that respond to hypoxia, play important roles in cancer development by participating in multiple processes, such as metabolism, proliferation, and angiogenesis. The Warburg phenomenon reflects a pseudo-hypoxic state that activates HIF-1α. In addition, a product of the Warburg effect, lactate, also induces HIF-1α. However, Warburg proposed that aerobic glycolysis occurs due to a defect in mitochondria. Moreover, both HIFs and mitochondrial dysfunction can lead to complex reprogramming of energy metabolism, including reduced mitochondrial oxidative metabolism, increased glucose uptake, and enhanced anaerobic glycolysis. Thus, there may be a connection between HIFs and mitochondrial dysfunction. In this review, we systematically discuss the crosstalk between HIFs and mitochondrial dysfunctions in cancer development. Above all, the stability and activity of HIFs are closely influenced by mitochondrial dysfunction related to tricarboxylic acid cycle, electron transport chain components, mitochondrial respiration, and mitochondrial-related proteins. Furthermore, activation of HIFs can lead to mitochondrial dysfunction by affecting multiple mitochondrial functions, including mitochondrial oxidative capacity, biogenesis, apoptosis, fission, and autophagy. In general, the regulation of tumorigenesis and development by HIFs and mitochondrial dysfunction are part of an extensive and cooperative network.

It has been known for many years that cellular metabolism within the solid tumour is markedly different from that of the corresponding normal tissue. The transcription factor hypoxia-inducible factor 1 (HIF1) has been implicated in regulating many of the genes that are responsible for the metabolic difference. However, it remains unclear how this 'aerobic glycolysis', originally described by Otto Warburg, offers tumour cells a growth advantage. As discussed in this Perspective, new data suggests that this metabolic switch may provide a benefit to the tumour not by increasing glycolysis but by decreasing mitochondrial activity. Aerobic glycolysis, or the 'Warburg effect', is a metabolic switch unique to tumour cells. But how might this change in tumour cell metabolism confer a growth advantage?

Both preclinical and clinical studies suggest that brief cycles of ischemia and reperfusion in the arm or leg may protect the heart against injury following prolonged coronary artery occlusion and reperfusion, a phenomenon known as remote ischemic preconditioning. Recent studies in mice indicate that increased plasma interleukin-10 (IL-10) levels play an important role in remote ischemic preconditioning induced by clamping the femoral artery for 5 min followed by 5 min of reperfusion for a total of three cycles. In this study, we demonstrate that remote ischemic preconditioning increases plasma IL-10 levels and decreases myocardial infarct size in wild-type mice but not in littermates that are heterozygous for a knockout allele at the locus encoding hypoxia-inducible factor (HIF) 1α. Injection of a recombinant adenovirus encoding a constitutively active form of HIF-1α into mouse hind limb muscle was sufficient to increase plasma IL-10 levels and decrease myocardial infarct size. Exposure of C2C12 mouse myocytes to cyclic hypoxia and reoxygenation rapidly increased levels of IL-10 mRNA, which was blocked by administration of the HIF-1 inhibitor acriflavine or by expression of short hairpin RNA targeting HIF-1α or HIF-1β. Chromatin immunoprecipitation assays demonstrated that binding of HIF-1 to the Il10 gene was induced when myocytes were subjected to cyclic hypoxia and reoxygenation. Taken together, these data indicate that HIF-1 activates Il10 gene transcription and is required for remote ischemic preconditioning.

Abstract Context Dapagliflozin and other SGLT2 inhibitors are known to increase hematocrit, possibly due to its diuretic effects and hemoconcentration. Objective Since type 2 diabetes is a proinflammatory state and since hepcidin, a known suppressor of erythropoiesis, is increased in proinflammatory states, we investigated the possibility that dapagliflozin suppresses hepcidin concentrations and thus increases erythropoiesis. Design Prospective, randomized, and placebo-controlled study. Setting Single endocrinology center. Patients Fifty-two obese type 2 diabetes patients. Intervention Patients were randomized (1:1) to either dapagliflozin (10 mg daily) or placebo for 12 weeks. Blood samples were collected before and after treatments and serum, plasma, and mononuclear cells (MNC) were prepared. Main Outcome Measure Hepcidin and other hematopoietic factors. Results Following dapagliflozin treatment, there was a significant fall in HbA1c and a significant increase in hemoglobin concentration and hematocrit. Dapagliflozin treatment significantly reduced circulating hepcidin and ferritin concentrations while causing a significant increase in levels of the hepcidin inhibitor, erythroferrone, and a transient increase in erythropoietin. Additionally, dapagliflozin increased plasma transferrin levels and expression of transferrin receptors 1 and 2 in MNC, while there was no change in the expression of the iron cellular transporter, ferroportin. Dapagliflozin treatment also caused a decrease in hypoxia-induced factor-1α expression in MNC while it increased the expression of its inhibitor, prolyl hydroxylase-2. There were no significant changes in any of these indices in the placebo group. Conclusions We conclude that dapagliflozin increases erythropoiesis and hematocrit through mechanisms that involve the suppression of hepcidin and the modulation of other iron regulatory proteins.

The tRNA-derived small RNAs (tsRNAs) can be categorized into two main groups: tRNA-derived fragments (tRFs) and tRNA-derived stress-induced RNAs (tiRNAs). Each group possesses specific molecular sizes, nucleotide compositions, and distinct physiological functions. Notably, hypoxia-inducible factor-1 (HIF-1), a transcriptional activator dependent on oxygen, comprises one HIF-1β subunit and one HIF-α subunit (HIF-1α/HIF-2α/HIF-3α). The activation of HIF-1 plays a crucial role in gene transcription, influencing key aspects of cancer biology such as angiogenesis, cell survival, glucose metabolism, and invasion. The involvement of HIF-1α activation has been demonstrated in numerous human diseases, particularly cancer, making HIF-1 an attractive target for potential disease treatments. Through a series of experiments, researchers have identified two tiRNAs that interact with the HIF-1 pathway, impacting disease development: 5′tiRNA-His-GTG in colorectal cancer (CRC) and tiRNA-Val in diabetic retinopathy (DR). Specifically, 5′tiRNA-His-GTG promotes CRC development by targeting LATS2, while tiRNA-Val inhibits Sirt1, leading to HIF-1α accumulation and promoting DR development. Clinical data have further indicated that certain tsRNAs’ expression levels are associated with the prognosis and pathological features of CRC patients. In CRC tumor tissues, the expression level of 5′tiRNA-His-GTG is significantly higher compared to normal tissues, and it shows a positive correlation with tumor size. Additionally, KEGG analysis has revealed multiple tRFs involved in regulating the HIF-1 pathway, including tRF-Val-AAC-016 in diabetic foot ulcers (DFU) and tRF-1001 in pathological ocular angiogenesis. This comprehensive article reviews the biological functions and mechanisms of tsRNAs related to the HIF-1 pathway in diseases, providing a promising direction for subsequent translational medicine research.

Cellular responses to low oxygen (hypoxia) are fundamental to normal physiology and to the pathology of many common diseases. Hypoxia-inducible factor (HIF) is central to this by enhancing the transcriptional activity of many hundreds of genes. The cellular response to HIF is cell-type-specific and is largely governed by the pre-existing epigenetic landscape. Prior to activation, HIF-binding sites and the promoters of HIF-target genes are already accessible, in contact with each other through chromatin looping and display markers of activity. However, hypoxia also modulates the epigenetic environment, both in parallel to and as a consequence of HIF activation. This occurs through a combination of oxygen-sensitive changes in enzyme activity, transcriptional activation of epigenetic modifiers, and localized recruitment to chromatin by HIF and activated RNApol2. These hypoxic changes in the chromatin environment may both contribute to and occur as a consequence of transcriptional regulation. Nevertheless, they have the capacity to both modulate and extend the transcriptional response to hypoxia.

Gemcitabine is commonly used to treat various cancer types, including human non-small cell lung cancer (NSCLC). However, even cases that initially respond rapidly commonly develop acquired resistance, limiting our ability to effectively treat advanced NSCLC. To gain insight for developing a strategy to overcome gemcitabine resistance, the present study investigated the mechanism of gemcitabine resistance in NSCLC according to the involvement of ATP-binding cassette subfamily B member 6 (ABCB6) and heme biosynthesis. First, an analysis of ABCB6 expression in human NSCLCs was found to be associated with poor prognosis and gemcitabine resistance in a hypoxia-inducible factor (HIF)-1-dependent manner. Further experiments showed that activation of HIF-1α/ABCB6 signaling led to intracellular heme metabolic reprogramming and a corresponding increase in heme biosynthesis to enhance the activation and accumulation of catalase. Increased catalase levels diminished the effective levels of reactive oxygen species, thereby promoting gemcitabine-based resistance. In a mouse NSCLC model, inhibition of HIF-1α or ABCB6, in combination with gemcitabine, strongly restrained tumor proliferation, increased tumor cell apoptosis, and prolonged animal survival. These results suggest that, in combination with gemcitabine-based chemotherapy, targeting HIF-1α/ABCB6 signaling could result in enhanced tumor chemosensitivity and, thus, may improve outcomes in NSCLC patients.