The roles of long non-coding RNAs in cancer metabolism remain largely unexplored. Here we identify FILNC1 (FoxO-induced long non-coding RNA 1) as an energy stress-induced long non-coding RNA by FoxO transcription factors. FILNC1 deficiency in renal cancer cells alleviates energy stress-induced apoptosis and markedly promotes renal tumor development. We show that FILNC1 deficiency leads to enhanced glucose uptake and lactate production through upregulation of c-Myc. Upon energy stress, FILNC1 interacts with AUF1, a c-Myc mRNA-binding protein, and sequesters AUF1 from binding c-Myc mRNA, leading to downregulation of c-Myc protein. FILNC1 is specifically expressed in kidney, and is downregulated in renal cell carcinoma; also, its low expression correlates with poor clinical outcomes in renal cell carcinoma. Together, our study not only identifies FILNC1 as a negative regulator of renal cancer with potential clinical value, but also reveals a regulatory mechanism by long non-coding RNAs to control energy metabolism and tumor development.FoxO are commonly down-regulated transcription factors and tumor suppressors in renal cell cancer (RCC). Here, the authors show that upon energy stress FoxOs induce the expression of the long non-coding RNA FILNC1, which inhibits survival of RCC by downregulating c-Myc and c-Myc-dependent metabolic rewiring.

Long non-coding RNAs (lncRNAs) contribute to colorectal cancer (CRC). However, the role of lncRNAs in CRC metabolism, especially glucose metabolism remains largely unknown. In this study, we identify a lncRNA, GLCC1, which is significantly upregulated under glucose starvation in CRC cells, supporting cell survival and proliferation by enhancing glycolysis. Mechanistically, GLCC1 stabilizes c-Myc transcriptional factor from ubiquitination by direct interaction with HSP90 chaperon and further specifies the transcriptional modification pattern on c-Myc target genes, such as LDHA, consequently reprogram glycolytic metabolism for CRC proliferation. Clinically, GLCC1 is associated with tumorigenesis, tumor size and predicts poor prognosis. Thus, GLCC1 is mechanistically, functionally, and clinically oncogenic in colorectal cancer. Targeting GLCC1 and its pathway may be meaningful for treating patients with colorectal cancer.

Background:Renal cell carcinoma (RCC) that originates from the proximal renal tubules is the most common cancer of the human kidney. Increasing circRNA/miRNA/mRNA networks have been found in RCC regulation. This study will explore the regulatory relation of circular RNA (circRNA) circ_0035483, microRNA-31-5p (miR-31-5p) and high mobility group A1 (HMGA1). Methods:The levels of circ_0035483, miR-31-5p and HMGA1 were measured by real-time polymerase chain reaction (qRT-PCR) or Western blot. Cell proliferation was determined using Cell Counting Kit-8 (CCK-8) and colony formation assays. Cell migration and invasion were assessed by transwell assay. HMGA1 and epithelial-mesenchymal transition (EMT)-related protein levels were quantified using Western blot. Glycolytic metabolism was evaluated by glucose consumption and lactate production. The interaction between targets was confirmed via dual-luciferase reporter, RNA immunoprecipitation (RIP) and RNA pull-down assays. experiment was performed through the establishment of xenograft models in mice. Results:Circ_0035483 expression was upregulated in RCC tissues and cells. The inhibitory effects on RCC cell proliferation, migration, invasion, EMT and glycolysis were induced after circ_0035483 was downregulated. MiR-31-5p was identified as a target of circ_0035483 and miR-31-5p upregulation was related to the function of circ_0035483 knockdown in RCC cells. Additionally, miR-31-5p targeted HMGA1 and inhibited the malignant behaviors of RCC cells by negatively regulating HMGA1. Moreover, HMGA1 expression was regulated by circ_0035483 via targeting miR-31-5p. Circ_0035483 also affected tumor growth by relying on the miR-31-5p/HMGA1 axis. Conclusion:These findings clarified that the tumor-promoting function of circ_0035483 in RCC was partly achieved by regulating the miR-31-5p/HMGA1 axis.

Caveolin-1 (CAV1) acts as a growth suppressor in various human malignancies, but its expression is elevated in many advanced cancers, suggesting the oncogenic switch of its role during tumor progression. To understand the molecular basis for the growth-promoting function of CAV1, we characterized its expression status, differential roles for tumor growth, and effect on glucose metabolism in colorectal cancers. Abnormal elevation of CAV1 was detected in a substantial fraction of primary tumors and cell lines and tightly correlated with promoter CpG sites hypomethylation. Depletion of elevated CAV1 led to AMPK activation followed by a p53-dependent G1 cell-cycle arrest and autophagy, suggesting that elevated CAV1 may contribute to ATP generation. Furthermore, CAV1 depletion downregulated glucose uptake, lactate accumulation, and intracellular ATP level, supporting that aerobic glycolysis is enhanced by CAV1. Consistently, CAV1 was shown to stimulate GLUT3 transcription via an HMGA1-binding site within the GLUT3 promoter. HMGA1 was found to interact with and activate the GLUT3 promoter and CAV1 increased the HMGA1 activity by enhancing its nuclear localization. Ectopic expression of HMGA1 increased glucose uptake, whereas its knockdown caused AMPK activation. In addition, GLUT3 expression was strongly induced by cotransfection of CAV1 and HMGA1, and its overexpression was observed predominantly in tumors harboring high levels of CAV1 and HMGA1. Together, these data show that elevated CAV1 upregulates glucose uptake and ATP production through HMGA1-mediated GLUT3 transcription, suggesting that CAV1 may render tumor cells growth advantages by enhancing aerobic glycolysis.

BACKGROUND & OBJECTIVES:Chromatin structure is the single most important feature that distinguishes a cancer cell from a normal cell histologically. Chromatin remodeling proteins regulate chromatin structure and high mobility group A (HMGA1) proteins are among the most abundant, nonhistone chromatin remodeling proteins found in cancer cells. These proteins include HMGA1a/HMGA1b isoforms, which result from alternatively spliced mRNA. The HMGA1 gene is overexpressed in cancer and high levels portend a poor prognosis in diverse tumors. HMGA1 is also highly expressed during embryogenesis and postnatally in adult stem cells. Overexpression of HMGA1 drives neoplastic transformation in cultured cells, while inhibiting HMGA1 blocks oncogenic and cancer stem cell properties. Hmga1 transgenic mice succumb to aggressive tumors, demonstrating that dysregulated expression of HMGA1 causes cancer in vivo. HMGA1 is also required for reprogramming somatic cells into induced pluripotent stem cells. HMGA1 proteins function as ancillary transcription factors that bend chromatin and recruit other transcription factors to DNA. They induce oncogenic transformation by activating or repressing specific genes involved in this process and an HMGA1 "transcriptome" is emerging. Although prior studies reveal potent oncogenic properties of HMGA1, we are only beginning to understand the molecular mechanisms through which HMGA1 functions. In this review, we summarize the list of putative downstream transcriptional targets regulated by HMGA1. We also briefly discuss studies linking HMGA1 to Alzheimer's disease and type-2 diabetes. CONCLUSION:Further elucidation of HMGA1 function should lead to novel therapeutic strategies for cancer and possibly for other diseases associated with aberrant HMGA1 expression.

Cancer stem cells are a subpopulation of cancer cells characterized by self-renewal ability, tumorigenesis and drug resistance. The aim of this study was to investigate the role of HMGA1, a chromatin remodeling factor abundantly expressed in many different cancers, in the regulation of cancer stem cells in ovarian cancer. Spheroid-forming cancer stem cells were isolated from A2780, SKOV3 and PA1 ovarian cancer cells by three-dimensional spheroid culture. Elevated expression of HMGA1 was observed in spheroid cells along with increased expression of stemness-related genes, such as SOX2, KLF4, ALDH, ABCB1 and ABCG2. Furthermore, spheroid A2780 cells, compared with adherent cells, showed higher resistance to chemotherapeutic agents such as paclitaxel and doxorubicin. HMGA1 knockdown in spheroid cells reduced the proliferative advantage and spheroid-forming efficiency of the cells and the expression of stemness-related genes. HMGA1 overexpression in adherent A2780 cells increased cancer stem cell properties, including proliferation, spheroid-forming efficiency and the expression of stemness-related genes. In addition, HMGA1 regulated ABCG2 promoter activity through HMGA1-binding sites. Knockdown of HMGA1 in spheroid cells reduced resistance to chemotherapeutic agents, whereas the overexpression of HMGA1 in adherent ovarian cancer cells increased resistance to chemotherapeutic agents in vitro. Furthermore, HMGA1-overexpressing A2780 cells showed a significant survival advantage after chemotherapeutic agent treatment in a xenograft tumorigenicity assay. Together, our results provide novel insights regarding the critical role of HMGA1 in the regulation of the cancer stem cell characteristics of ovarian cancer cells, thus suggesting that HMGA1 may be an important target in the development of therapeutics for ovarian cancer patients.

The high mobility group A1 (HMGA1) gene plays an important role in numerous malignant cancers. HMGA1 is an oncofoetal gene, and we have a certain understanding of the biological function of HMGA1 based on its activities in various neoplasms. As an architectural transcription factor, HMGA1 remodels the chromatin structure and promotes the interaction between transcriptional regulatory proteins and DNA in different cancers. Through analysis of the molecular mechanism of HMGA1 and clinical studies, emerging evidence indicates that HMGA1 promotes the occurrence and metastasis of cancer. Within a similar location or the same genetic background, the function and role of HMGA1 may have certain similarities. In this paper, to characterize HMGA1 comprehensively, research on various types of tumours is discussed to further understanding of the function and mechanism of HMGA1. The findings provide a more reliable basis for classifying HMGA1 function according to the tumour location. In this review, we summarize recent studies related to HMGA1, including its structure and oncogenic properties, its major functions in each cancer, its upstream and downstream regulation associated with the tumourigenesis and metastasis of cancer, and its potential as a biomarker for clinical diagnosis of cancer.

High-mobility group A1 (HMGA1), an architectural transcription factor, participates in different human tumors' biological progression. HMGA1 overexpression is associated with malignant cellular behavior in a wide range of cancers but the underlying mechanism remains poorly illuminated. In this study, we showed PI3K/Akt/MMP9 pathway activity could be positively regulated by HMGA1 using western blotting, real-time polymerase chain reaction (RT-PCR) and immunochemistry both in vitro (C918 and MUM-2B cell lines) and in vivo (xenograft mouse model). Later, MiRTarBase was used to identify the relationship between HMGA1 and miR-222-3p, we found miR-222 is positively regulated by HMGA1. Moreover, the proliferation and migration of UM cells significantly increased in the miR-222 mimics group and decreased in the miR-222 inhibitor group detected by the Annexin V-FITC apoptosis detection kit, CCK-8 and scratch wound-healing. The p-PI3K, p-Akt and MMP9 expressions were elevated in UM cells transfected with miR-222 mimics, and suppressed in the miR-222 inhibitor group. Together, our study highlights that HMGA1 acts as a pivotal regulator in UM tumor growth, proposing a critical viewpoint that HMGA1 expedites progression through the PI3K/Akt/MMP9 pathway and oncogenic miR-222 in UM.

Endometrioid endometrial carcinomas (EEC) are the most common malignant gynecologic tumors. Despite the increase in EEC molecular knowledge, the identification of new biomarkers involved in disease's development and/or progression would represent an improvement in its course. High-mobility group A protein (HMGA) family members are frequently overexpressed in a wide range of malignancies, correlating with a poor prognosis. Thus, the aim of this study was to analyze HMGA1 and HMGA2 expression pattern and their potential role as EEC biomarkers. HMGA1 and HMGA2 expression was initially evaluated in a series of 46 EEC tumors (stages IA to IV), and the findings were then validated in The Cancer Genome Atlas (TCGA) EEC cohort, comprising 381 EEC tumors (stages IA to IV). Our results reveal that HMGA1 and HMGA2 mRNA and protein are overexpressed in ECC, but only expression is associated with increased histological grade and tumor size. Moreover, but not overexpression was identified as a negative prognostic factor to EEC patients. Finally, a positive correlation between expression of pseudogenes- and -and HMGA1 itself was detected, suggesting HMGA1 pseudogenes may play a role in HMGA1 expression regulation in EEC. Thus, these results indicate that overexpression possesses a potential role as a prognostic biomarker for EEC.

The high mobility group A1 (HMGA1) protein, an architectural transcription factor, is profoundly implicated in the pathogenesis and progression of multiple malignant tumors. Reprogrammed energy metabolism is a hallmark of diverse types of cancer cells. However, little is known about the regulatory role of HMGA1 in aerobic glycolysis. In this study, we found that HMGA1 was highly expressed in many types of human cancers including gastric cancer and predicted a poor prognosis. However, high HMGA1 expression was not correlated with TNM stages. Gene set enrichment analysis result suggested a link between HMGA1 expression and glycolytic phenotype in gastric cancer. Genetic silencing of HMGA1 significantly inhibited gastric cancer glycolytic activity as revealed by reduced glucose uptake, lactate release, and extracellular acidification ratio. In addition, cell proliferation and invasive capacity of gastric cancer cells were also suppressed by HMGA1 knockdown. Mechanistically, the key glycolysis regulator c-Myc was identified as a downstream target of HMGA1. In gastric cancer patients, HMGA1 and c-Myc expression were closely associated with the glycolysis gene signature. Taken together, our findings identify a novel function of HMGA1 in regulating aerobic glycolysis in gastric cancer.

OBJECTIVES:Although uterine cancer is the fourth most common cause for cancer death in women worldwide, the molecular underpinnings of tumor progression remain poorly understood. The High Mobility Group A1 (HMGA1) gene is overexpressed in aggressive cancers and high levels portend adverse outcomes in diverse tumors. We previously reported that Hmga1a transgenic mice develop uterine tumors with complete penetrance. Because HMGA1 drives tumor progression by inducing MatrixMetalloproteinase (MMP) and other genes involved in invasion, we explored the HMGA1-MMP-2 pathway in uterine cancer. METHODS:To investigate MMP-2 in uterine tumors driven by HMGA1, we used a genetic approach with mouse models. Next, we assessed HMGA1 and MMP-2 expression in primary human uterine tumors, including low-grade carcinomas (endometrial endometrioid) and more aggressive tumors (endometrial serous carcinomas, uterine carcinosarcomas/malignant mesodermal mixed tumors). RESULTS:Here, we report for the first time that uterine tumor growth is impaired in Hmga1a transgenic mice crossed on to an Mmp-2 deficient background. In human tumors, we discovered that HMGA1 is highest in aggressive carcinosarcomas and serous carcinomas, with lower levels in the more indolent endometrioid carcinomas. Moreover, HMGA1 and MMP-2 were positively correlated, but only in a subset of carcinosarcomas. HMGA1 also occupies the MMP-2 promoter in human carcinosarcoma cells. CONCLUSIONS:Together, our studies define a novel HMGA1-MMP-2 pathway involved in a subset of human carcinosarcomas and tumor progression in murine models. Our work also suggests that targeting HMGA1 could be effective adjuvant therapy for more aggressive uterine cancers and provides compelling data for further preclinical studies.

OBJECTIVE:To investigate the role of micro ribonucleic acid (miR)-195 in acquired resistance to 5-fluorouracil (5-FU) in gastric cancer and its potential mechanism. MATERIALS AND METHODS:The drug resistance of AGS/5-FU and SGC-7901/5-FU cells compared with their parental cells was verified via methyl thiazolyl tetrazolium (MTT) assay, and the expression levels of miR-195 and high-mobility group protein A1 (HMGA1) in AGS/5-FU and SGC-7901/5-FU cells were detected via quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) and Western blotting. MiR-195 mimic and miR-195 inhibitor were transfected into AGS/5-FU and AGS cells, respectively, the changes in HMGA1 expression were detected via qRT-PCR and Western blotting, and the sensitivity of cells to 5-FU after transfection was detected via MTT assay. After the wild-type and mutant-type luciferase reporter plasmids of HMGA1 were co-transfected with miR-195 mimic or miR-195 NC into cells, the luciferase activity was analyzed using the dual-luciferase reporter system. Finally, the rescue experiment was performed to confirm whether the changes in HMGA1 expression promote the formation of drug resistance in gastric cancer. RESULTS:Both AGS/5-FU and SGC-7901/5-FU cells were significantly resistant to 5-FU compared with their parental cells, and miR-195 was down-regulated in AGS/5-FU and SGC-7901/5-FU cells, while HMGA1 was up-regulated in AGS and SGC-7901 cells. The transfection with miR-195 mimic could suppress the expression level of HMGA1 in AGS/5-FU cells, while the transfection with miR-195 inhibitor could up-regulate the expression level of HMGA1 in AGS cells. Moreover, miR-195 could bind to HMGA1 3'-untranslated region (3'UTR) in a targeted way, thereby inhibiting its expression. It was confirmed via a rescue experiment that the changes in HMGA1 expression promoted the formation of drug resistance in gastric cancer. CONCLUSIONS:The down-regulation of miR-195 induces the resistance to 5-FU in gastric cancer through promoting the expression of HMGA1.

PURPOSE:The high mobility group A1 (HMGA1) chromatin remodeling protein is required for metastatic progression and cancer stem cell properties in preclinical breast cancer models, although its role in breast carcinogenesis has remained unclear. To investigate HMGA1 in primary breast cancer, we evaluated immunoreactivity score (IRS) in tumors from a large cohort of Asian women; HMGA1 gene expression was queried from two independent Western cohorts. METHODS:HMGA1 IRS was generated from breast tumors in Korean women as the product of staining intensity (weak = 1, moderate = 2, strong = 3) and percent positive cells (< 5% = 0, 5-30% = 1, 30-60% = 2, > 60% = 3), and stratified into three groups: low (< 3), intermediate (3-6), high (> 6). We assessed HMGA1 and estrogen receptor (ESR1) gene expression from two large databases (TCGA, METABRIC). Overall survival was ascertained from the METABRIC cohort. RESULTS:Among 540 primary tumors from Korean women (181 ER-negative, 359 ER-positive), HMGA1 IRS was < 3 in 89 (16.5%), 3-6 in 215 (39.8%), and > 6 in 236 (43.7%). High HMGA1 IRS was associated with estrogen receptor (ER)-negativity (χ = 12.07; P = 0.002) and advanced nuclear grade (χ = 12.83; P = 0.012). In two large Western cohorts, the HMGA1 gene was overexpressed in breast cancers compared to non-malignant breast tissue (P < 0.0001), including Asian, African American, and Caucasian subgroups. HMGA1 was highest in ER-negative tumors and there was a strong inverse correlation between HMGA1 and ESR1 gene expression (Pearson r = - 0.60, P < 0.0001). Most importantly, high HMGA1 predicted decreased overall survival (P < 0.0001) for all women with breast cancer and further stratified ER-positive tumors into those with inferior outcomes. CONCLUSIONS:Together, our results suggest that HMGA1 contributes to estrogen-independence, tumor progression, and poor outcomes. Moreover, further studies are warranted to determine whether HMGA1 could serve as a prognostic marker and therapeutic target for women with breast cancer.

High-mobility group AT-hook1 (HMGA1, formerly HMG-I/Y), an architectural transcription factor, participates in a number of tumor biological processes. However, its effect on cervical cancer remains largely indistinct. In this study, we found that HMGA1 was generally overexpressed in cervical cancer tissues and was positively correlated with lymph node metastasis and advanced clinical stage. Via exogenously increasing or decreasing the expression of HMGA1, we showed that HMGA1 affected the proliferation, colony formation, migration and invasion of cervical cancer cells in vitro. Rescue experiments suggested that miR-221/222 could partly reverse HMGA1-mediated migration and invasion processes. Mechanistically, we discovered that HMGA1 accelerated the G1/S phase transition by regulating the expression of cyclin D1 and cyclin E1, which was consistent with the results of the in vivo experiment. Furthermore, we found that HMGA1 regulated the expression of the miR-221/222 cluster at the transcriptional level and that miR-221/222 targeted the 3'UTR of tissue inhibitor of metalloproteinases 3(TIMP3). We propose a fresh perspective that HMGA1 participates in the migration and invasion process via the miR-221/222-TIMP3-MMP2/MMP9 axis in cervical cancer. In summary, our study identified a critical role played by HMGA1 in the progression of cervical cancer and the potential mechanisms by which exerts its effects, suggesting that targeting HMGA1-related pathways could be conducive to the therapies for cervical cancer.