HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis.

Esophageal carcinoma is amongst the prevalent malignancies worldwide, characterized by unclear molecular classifications and varying clinical outcomes. The PI3K/AKT/mTOR signaling, one of the frequently perturbed dysregulated pathways in human malignancies, has instigated the development of various inhibitory agents targeting this pathway, but many ESCC patients exhibit intrinsic or adaptive resistance to these inhibitors. Here, we aim to explore the reasons for the insensitivity of ESCC patients to mTOR inhibitors. We assessed the sensitivity to rapamycin in various ESCC cell lines by determining their respective IC50 values and found that cells with a low level of HMGA1 were more tolerant to rapamycin. Subsequent experiments have supported this finding. Through a transcriptome sequencing, we identified a crucial downstream effector of HMGA1, FKBP12, and found that FKBP12 was necessary for HMGA1-induced cell sensitivity to rapamycin. HMGA1 interacted with ETS1, and facilitated the transcription of FKBP12. Finally, we validated this regulatory axis in in vivo experiments, where HMGA1 deficiency in transplanted tumors rendered them resistance to rapamycin. Therefore, we speculate that mTOR inhibitor therapy for individuals exhibiting a reduced level of HMGA1 or FKBP12 may not work. Conversely, individuals exhibiting an elevated level of HMGA1 or FKBP12 are more suitable candidates for mTOR inhibitor treatment.

HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS): A Spanish Group for Research on Sarcomas (GEIS) study.

HMGA1 is a structural epigenetic chromatin factor that has been associated with tumor progression and drug resistance. Here, we reported the prognostic/predictive value of HMGA1 for trabectedin in advanced soft-tissue sarcoma (STS) and the effect of inhibiting HMGA1 or the mTOR downstream pathway in trabectedin activity. The prognostic/predictive value of HMGA1 expression was assessed in a cohort of 301 STS patients at mRNA (n = 133) and protein level (n = 272), by HTG EdgeSeq transcriptomics and immunohistochemistry, respectively. The effect of HMGA1 silencing on trabectedin activity and gene expression profiling was measured in leiomyosarcoma cells. The effect of combining mTOR inhibitors with trabectedin was assessed on cell viability in vitro studies, whereas in vivo studies tested the activity of this combination. HMGA1 mRNA and protein expression were significantly associated with worse progression-free survival of trabectedin and worse overall survival in STS. HMGA1 silencing sensitized leiomyosarcoma cells for trabectedin treatment, reducing the spheroid area and increasing cell death. The downregulation of HGMA1 significantly decreased the enrichment of some specific gene sets, including the PI3K/AKT/mTOR pathway. The inhibition of mTOR, sensitized leiomyosarcoma cultures for trabectedin treatment, increasing cell death. In in vivo studies, the combination of rapamycin with trabectedin downregulated HMGA1 expression and stabilized tumor growth of 3-methylcholantrene-induced sarcoma-like models. HMGA1 is an adverse prognostic factor for trabectedin treatment in advanced STS. HMGA1 silencing increases trabectedin efficacy, in part by modulating the mTOR signaling pathway. Trabectedin plus mTOR inhibitors are active in preclinical models of sarcoma, downregulating HMGA1 expression levels and stabilizing tumor growth.

LINC00665 target let-7i/HMGA1 promotes the proliferation and invasion of hepatoma cells.

OBJECTIVES: Our group previously found that LINC00665 was upregulated in hepatocellular carcinoma (HCC) tissues through database analysis; however, the potential molecular mechanism of LINC00665 in HCC progression still needs further study. METHODS: qRTPCR was performed to determine the differential expression of LINC00665 and let-7i in HCC cells. Dual-luciferase reporter assays were performed to analyze the interaction of LINC00665 and let-7i. CCK-8 assays, scratch assays, Transwell invasion assays, qRTPCR and western blotting were performed to determine the regulatory mechanism of LINC00665/let-7i/HMGA1 in HCC cells. RESULTS: LINC00665 was upregulated in HCC cells compared with normal hepatocytes. A potential binding site between LINC00665 and let-7i was confirmed by dual-luciferase reporter assay. In HCC cells, inhibition of LINC00665 significantly reduced cell proliferation, migration and invasion ability via the let-7i/HMGA1 signaling axis. CONCLUSION: LINC00665 promotes the proliferation and invasion of HCC cells via the let-7i/HMGA1 signaling axis.

HMGA1 drives chemoresistance in esophageal squamous cell carcinoma by suppressing ferroptosis.

Chemotherapy is a primary treatment for esophageal squamous cell carcinoma (ESCC). Resistance to chemotherapeutic drugs is an important hurdle to effective treatment. Understanding the mechanisms underlying chemotherapy resistance in ESCC is an unmet medical need to improve the survival of ESCC. Herein, we demonstrate that ferroptosis triggered by inhibiting high mobility group AT-hook 1 (HMGA1) may provide a novel opportunity to gain an effective therapeutic strategy against chemoresistance in ESCC. HMGA1 is upregulated in ESCC and works as a key driver for cisplatin (DDP) resistance in ESCC by repressing ferroptosis. Inhibition of HMGA1 enhances the sensitivity of ESCC to ferroptosis. With a transcriptome analysis and following-up assays, we demonstrated that HMGA1 upregulates the expression of solute carrier family 7 member 11 (SLC7A11), a key transporter maintaining intracellular glutathione homeostasis and inhibiting the accumulation of malondialdehyde (MDA), thereby suppressing cell ferroptosis. HMGA1 acts as a chromatin remodeling factor promoting the binding of activating transcription factor 4 (ATF4) to the promoter of SLC7A11, and hence enhancing the transcription of SLC7A11 and maintaining the redox balance. We characterized that the enhanced chemosensitivity of ESCC is primarily attributed to the increased susceptibility of ferroptosis resulting from the depletion of HMGA1. Moreover, we utilized syngeneic allograft tumor models and genetically engineered mice of HMGA1 to induce ESCC and validated that depletion of HMGA1 promotes ferroptosis and restores the sensitivity of ESCC to DDP, and hence enhances the therapeutic efficacy. Our finding uncovers a critical role of HMGA1 in the repression of ferroptosis and thus in the establishment of DDP resistance in ESCC, highlighting HMGA1-based rewiring strategies as potential approaches to overcome ESCC chemotherapy resistance. Schematic depicting that HMGA1 maintains intracellular redox homeostasis against ferroptosis by assisting ATF4 to activate SLC7A11 transcription, resulting in ESCC resistance to chemotherapy.

The role of high mobility group AT-hook 1 in viral infections: Implications for cancer pathogenesis.

The crucial role of high mobility group AT-hook 1 (HMGA1) proteins in nuclear processes such as gene transcription, DNA replication, and chromatin remodeling is undeniable. Elevated levels of HMGA1 have been associated with unfavorable clinical outcomes and adverse differentiation status across various cancer types. HMGA1 regulates a diverse array of biological pathways, including tumor necrosis factor-alpha/nuclear factor-kappa B (TNF-α/NF-κB), epidermal growth factor receptor (EGFR), Hippo, Rat sarcoma/extracellular signal-regulated kinase (Ras/ERK), protein kinase B (Akt), wingless-related integration site/beta-catenin (Wnt/beta-catenin), and phosphoinositide 3-kinase/protein kinase B (PI3-K/Akt). While researchers have extensively investigated tumors in the reproductive, digestive, urinary, and hematopoietic systems, mounting evidence suggests that HMGA1 plays a critical role as a tumorigenic factor in tumors across all functional systems. Given its broad interaction network, HMGA1 is an attractive target for viral manipulation. Some viruses, including herpes simplex virus type 1, human herpesvirus 8, human papillomavirus, JC virus, hepatitis B virus, human immunodeficiency virus type 1, severe acute respiratory syndrome Coronavirus 2, and influenza viruses, utilize HMGA1 influence for infection. This interaction, particularly in oncogenesis, is crucial. Apart from the direct oncogenic effect of some of the mentioned viruses, the hit-and-run theory postulates that viruses can instigate cancer even before being completely eradicated from the host cell, implying a potentially greater impact of viruses on cancer development than previously assumed. This review explores the interplay between HMGA1, viruses, and host cellular machinery, aiming to contribute to a deeper understanding of viral-induced oncogenesis, paving the way for innovative strategies in cancer research and treatment.

Circ_UBAP2 exacerbates proliferation and metastasis of OS via targeting miR-665/miR-370-3p/HMGA1 axis.

Circ_UBAP2 is extensively engaged in regulating the development of various malignancies, containing osteosarcoma (OS). However, its biological significance and function are not fully understood. In this study, we found that circ_UBAP2 and HMGA1 levels were up-regulated, and miR-370-3p and miR-665 expressions were decreased in osteosarcoma tissues. Inhibition of circ_UBAP2 or HMGA1 expression in OS cells, cell viability, invasion and migration abilitities were notably hindered, and cell apoptosis abilities were increased. Bioinformatics analysis predicted that miR-665 and miR-370-3p were the downstream targets of circ_UBAP2, and the dual luciferase experiment demonstrated the correlation between them. In addition, inhibition of miR-665 and miR-370-3p expression could significantly reverse the impact of knocking down circ_UBAP2 on OS cells. HMGA1 was discovered to become the downstream target of both miR-665 and miR-370-3p. It was shown that over-expression of miR-665 or miR-370-3p notably stimulated the cell growth, invasion, and migration of osteosarcoma cells, while hindered cell apoptosis. Nevertheless, this effect could be reversed by concurrent over-expression of HMGA1. Our data strongly prove that circ_UBAP2 makes a vital impact on promoting the proliferation, invasion as well as migration of osteosarcoma cells via down-regulating the level of miR-665 and miR-370-3p, and later up-regulating the level of HMGA1. In conclusion, circ_UBAP2 is upregulated in osteosarcoma, and it competitively adsorbs miR-370-3p and miR-665, resulting in up-regulation of HMGA1, thus promoting OS development.

TFAP2A activates HMGA1 to promote glycolysis and lung adenocarcinoma progression.

BACKGROUND: Lung cancer is the most common cancer in the world. High Mobility Group AT-Hook 1 (HMGA1) is found to be associated with the glycolytic pathway in a variety of cancers, and abnormal glycolysis function is one of the important characteristics of cancer cells. Therefore, this paper discusses the effect of HMGA1 on glycolysis of lung adenocarcinoma (LUAD) cells METHODS: The mRNA expression data were downloaded from TCGA-LUAD database. Groups were set according to the median expression of HMGA1, followed by GSEA enrichment analysis. The upstream transcriptional regulators of HMGA1 were predicted by bioinformatics. The correlation between HMGA1 and Transcription Factor AP-2 Alpha (TFAP2A) and their expression in LUAD tissues were analyzed as well. mRNA expression levels of HMGA1 and TFAP2A were detected by qRT-PCR. The binding of HMGA1 and TFAP2A was demonstrated by ChIP and dual luciferase reporter assays. Cell function experiments were utilized to assay proliferation, apoptosis, glycolysis ability of LUAD cells, and glycolysis-related protein expression in each treatment group. RESULTS: HMGA1 was highly expressed in LUAD patients' tissues and enriched in the glycolytic pathway. Additionally, silencing HMGA1 markedly hampered cell proliferation and glycolysis, and promoted cell apoptosis. The upstream transcriptional regulator TFAP2A was predicted to be highly expressed in LUAD. ChIP and dual luciferase reporter assays confirmed the targeted relationship between HMGA1 and TFAP2A. Cell rescue assay confirmed that TFAP2A promoted glycolysis and LUAD progression by activating HMGA1. CONCLUSION: TFAP2A promotes glycolysis, proliferation and hampers apoptosis of LUAD cells by stimulating HMGA1. Hence, TFAP2A/HMGA1 may be a feasible therapeutic target for LUAD. AVAILABILITY OF DATA AND MATERIALS: All the data within this manuscript could be gotten from corresponding author at reasonable request.

YWHAH activates the HMGA1/PI3K/AKT/mTOR signaling pathway by positively regulating Fra-1 to affect the proliferation of gastric cancer cells.

Fos-related antigen 1 (Fra-1) is a nuclear transcription factor that regulates cell growth, differentiation, and apoptosis. It is involved in the proliferation, invasion, apoptosis and epithelial mesenchymal transformation of malignant tumor cells. Fra-1 is highly expressed in gastric cancer (GC), affects the cycle distribution and apoptosis of GC cells, and participates in GC occurrence and development. However, the detailed mechanism of Fra-1 in GC is unclear, such as the identification of Fra-1-interacting proteins and their role in GC pathogenesis. In this study, we identified tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein eta (YWHAH) as a Fra-1-interacting protein in GC cells using co-immunoprecipitation combined with liquid chromatography-tandem mass spectrometry. Experiments showed that YWHAH positively regulated Fra-1 mRNA and protein expression, and affected GC cell proliferation. Whole proteome analysis showed that Fra-1 affected the activity of the high mobility group AT-hook 1 (HMGA1)/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway in GC cells. Western blotting and flow cytometry confirmed that YWHAH activated HMGA1/PI3K/AKT/mTOR signaling pathway by positively regulating Fra-1 to affect GC cell proliferation. These results will help to discover new molecular targets for the early diagnosis, treatment, and prognosis prediction of GC.

Targeting HMGA1 contributes to immunotherapy in aggressive breast cancer while suppressing EMT.

Metastasis is an obstacle to the clinical treatment of aggressive breast cancer (BC). Studies have shown that high mobility group A1 (HMGA1) is abnormally expressed in various cancers and mediates tumor proliferation and metastasis. Here, we provided more evidence that HMGA1 mediated epithelial to mesenchymal transition (EMT) through the Wnt/ß-catenin pathway in aggressive BC. More importantly, HMGA1 knockdown enhanced antitumor immunity and improved the response to immune checkpoint blockade (ICB) therapy by upregulating programmed cell death ligand 1 (PD-L1) expression. Simultaneously, we revealed a novel mechanism by which HMGA1 and PD-L1 were regulated by the PD-L1/HMGA1/Wnt/ß-catenin negative feedback loop in aggressive BC. Taken together, we believe that HMGA1 can serve as a target for the dual role of anti-metastasis and enhancing immunotherapeutic responses.

HMGA1 induces FGF19 to drive pancreatic carcinogenesis and stroma formation.

High mobility group A1 (HMGA1) chromatin regulators are upregulated in diverse tumors where they portend adverse outcomes, although how they function in cancer remains unclear. Pancreatic ductal adenocarcinomas (PDACs) are highly lethal tumors characterized by dense desmoplastic stroma composed predominantly of cancer-associated fibroblasts and fibrotic tissue. Here, we uncover an epigenetic program whereby HMGA1 upregulates FGF19 during tumor progression and stroma formation. HMGA1 deficiency disrupts oncogenic properties in vitro while impairing tumor inception and progression in KPC mice and subcutaneous or orthotopic models of PDAC. RNA sequencing revealed HMGA1 transcriptional networks governing proliferation and tumor-stroma interactions, including the FGF19 gene. HMGA1 directly induces FGF19 expression and increases its protein secretion by recruiting active histone marks (H3K4me3, H3K27Ac). Surprisingly, disrupting FGF19 via gene silencing or the FGFR4 inhibitor BLU9931 recapitulates most phenotypes observed with HMGA1 deficiency, decreasing tumor growth and formation of a desmoplastic stroma in mouse models of PDAC. In human PDAC, overexpression of HMGA1 and FGF19 defines a subset of tumors with extremely poor outcomes. Our results reveal what we believe is a new paradigm whereby HMGA1 and FGF19 drive tumor progression and stroma formation, thus illuminating FGF19 as a rational therapeutic target for a molecularly defined PDAC subtype.

Long non-coding RNA MYU promotes ovarian cancer cell proliferation by sponging miR-6827-5p and upregulating HMGA1.

Background: Long non-coding RNAs (lncRNAs) have been confirmed to play vital roles in tumorigenesis. LncRNA MYU has recently been reported as an oncogene in several kinds of tumors. However, MYU's expression status and potential involvement in ovarian cancer (OC) remain unclear. In this study, we explored the underlying role of MYU in OC. Methods and results: The expression of MYU was upregulated in OC tissues, and MYU's overexpression was significantly correlated with the FIGO stage and lymphatic metastasis. Knockdown of MYU inhibited cell proliferation in SKOV3 and A2780 cells. Mechanistically, MYU directly interacted with miR-6827-5p in OC cells; HMGA1 is a downstream target gene of miR-6827-5p. Furthermore, MYU knockdown increased the expression of miR-6827-5p and decreased the expression of HMGA1. Restoration of HMGA1 expression reversed the influence on cell proliferation caused by MYU knockdown. Conclusion: MYU functions as a ceRNA that positively regulates HMGA1 expression by sponging miR-6827-5p in OC cells, which may provide a potential target and biomarker for the diagnosis or prognosis of OC.

ST8SIA6-AS1 contributes to hepatocellular carcinoma progression by targeting miR-142-3p/HMGA1 axis.

Hepatocellular carcinoma (LIHC) accounts for 90% of all liver cancers and is a serious health concern worldwide. Long noncoding RNAs (lncRNAs) have been observed to sponge microRNAs (miRNAs) and participate in the biological processes of LIHC. This study aimed to evaluate the role of the ST8SIA6-AS1-miR-142-3p-HMGA1 axis in regulating LIHC progression. RT-qPCR and western blotting were performed to determine the levels of ST8SIA6-AS1, miR-142-3p, and HMGA1 in LIHC. The relationship between ST8SIA6-AS1, miR-142-3p, and HMGA1 was assessed using luciferase assay. The role of the ST8SIA6-AS1-miR-142-3p-HMGA1 axis was evaluated in vitro using LIHC cells. Expression of ST8SIA6-AS1 and HMGA1 was significantly upregulated, whereas that of miR-142-3p was markedly lowered in LIHC specimens and cells. ST8SIA6-AS1 accelerated cell growth, invasion, and migration and suppressed apoptosis in LIHC. Notably, ST8SIA6-AS1 inhibited HMGA1 expression by sponging miR-142-3p in LIHC cells. In conclusion, sponging of miR-142-3p by ST8SIA6-AS1 accelerated the growth of cells while preventing cell apoptosis in LIHC cells, and the inhibitory effect of miR-142-3p was abrogated by elevating HMGA1 expression. The ST8SIA6-AS1-miR-142-3p-HMGA1 axis represents a potential target for the treatment of patients with LIHC.

XIST/let-7i/HMGA1 axis maintains myofibroblasts activities in oral submucous fibrosis.

Long non-coding RNA XIST promotes the development of various types of head and neck cancers, but its role in the progression of precancerous oral submucous fibrosis (OSF) has not been determined yet. As such, we aimed to examine whether XIST implicates in the regulation of myofibroblast activation. Our results showed that the expression of XIST was upregulated in OSF tissues and fibrotic buccal mucosal fibroblasts (fBMFs), and the silencing of XIST downregulated several myofibroblasts features. We demonstrated that elevation of let-7i after inhibition of XIST may lead to reduced myofibroblast activation. On the contrary, overexpression of high mobility group AT-Hook 1 (HMGA1) following the suppression of let-7i may result in enhanced myofibroblast activities. Moreover, we showed that the suppressive effect of silencing of XIST on myofibroblasts hallmarks was reversed by let-7i inhibition or HMGA1 overexpression, suggesting the pro-fibrotic property of XIST was mediated by downregulation of let-7i and upregulation of HMGA1. These findings revealed that myofibroblast activation of fBMFs may attribute to the alteration of the XIST/let-7i/HMGA1 axis. Therapeutic approaches to target this axis may serve as a promising direction to ameliorate the malignant progression of OSF.

Association between HMGA1 and immunosuppression in hepatocellular carcinoma: A comprehensive bioinformatics analysis.

The high mobility group A1 (HMGA1) gene is overexpressed in malignant tumors, and its expression level correlates with the progression and metastasis of tumors. However, the specific role of HMGA1 in hepatocellular carcinoma (HCC) and relevant influencing approaches in tumor immunity remain unclear. In this study, the expression and clinical significance of HMGA1 in HCC immunity were analyzed. The expression levels of HMGA1 mRNA and protein in HCC tissue and normal liver tissue were analyzed based on the cancer genome atlas, the gene expression omnibus and the Human Protein Atlas databases. The correlation between HMGA1 and clinicopathological factors was analyzed, and survival was estimated based on the expression of HMGA1. Gene set cancer analysis and the TISIDB database were used to identify tumor-infiltrating immune cells and immune inhibitors. Gene set enrichment analysis was performed to determine the involved signaling pathway. The HMGA1 genetic alterations were identified with the cBioPortal for Cancer Genomics. The expression of HMGA1 mRNA and protein was significantly higher in HCC tissue and negatively correlated with survival. Neutrophils, Th17 cells, several immune inhibitors, and signaling pathways were positively correlated with the expression of HMGA1. Amplification was the main type of genetic alteration in HMGA1. These findings demonstrate that HMGA1 can be a therapeutic target and a potential biomarker to predict the prognosis of patients with HCC. HMGA1 may affect the progression of HCC by suppressing the immune function of these patients.

3'RNA and whole-genome sequencing of archival uterine leiomyomas reveal a tumor subtype with chromosomal rearrangements affecting either HMGA2, HMGA1, or PLAG1.

Uterine leiomyomas, or fibroids, are very common smooth muscle tumors that arise from the myometrium. They can be divided into distinct molecular subtypes. We have previously shown that 3'RNA-sequencing is highly effective in classifying archival formalin-fixed paraffin-embedded (FFPE) leiomyomas according to the underlying mutation. In this study, we performed 3'RNA-sequencing with 111 FFPE leiomyomas previously classified as negative for driver alterations in mediator complex subunit 12 (MED12), high mobility group AT-hook 2 (HMGA2), and fumarate hydratase (FH) by Sanger sequencing and immunohistochemistry. This revealed 43 tumors that displayed expression features typically seen in HMGA2-positive tumors, including overexpression of PLAG1. We explored 12 such leiomyomas by whole-genome sequencing to identify their underlying genomic drivers and to evaluate the feasibility of detecting chromosomal driver alterations from FFPE material. Four tumors with significant HMGA2 overexpression at the protein-level served as controls. We identified chromosomal rearrangements targeting either HMGA2, HMGA1, or PLAG1 in all 16 tumors, demonstrating that it is possible to detect chromosomal driver alterations in archival leiomyoma specimens as old as 18 years. Furthermore, two tumors displayed biallelic loss of DEPDC5 and one tumor harbored a COL4A5-COL4A6 deletion. These observations suggest that instead of only HMGA2-positive leiomyomas, a distinct leiomyoma subtype is characterized by rearrangements targeting either HMGA2, HMGA1, or PLAG1. The results indicate that the frequency of HMGA2-positive leiomyomas may be higher than estimated in previous studies where immunohistochemistry has been used. This study also demonstrates the feasibility of detecting chromosomal driver alterations from archival FFPE material.

The Chromatin Regulator HMGA1a Undergoes Phase Separation in the Nucleus.

The protein high mobility group A1 (HMGA1) is an important regulator of chromatin organization and function. However, the mechanisms by which it exerts its biological function are not fully understood. Here, we report that the HMGA isoform, HMGA1a, nucleates into foci that display liquid-like properties in the nucleus, and that the protein readily undergoes phase separation to form liquid condensates in vitro. By bringing together machine-leaning modelling, cellular and biophysical experiments and multiscale simulations, we demonstrate that phase separation of HMGA1a is promoted by protein-DNA interactions, and has the potential to be modulated by post-transcriptional effects such as phosphorylation. We further show that the intrinsically disordered C-terminal tail of HMGA1a significantly contributes to its phase separation through electrostatic interactions via AT hooks 2 and 3. Our work sheds light on HMGA1 phase separation as an emergent biophysical factor in regulating chromatin structure.

Polymorphism and expression of the HMGA1 gene and association with tail fat deposition in Hu sheep.

Hu sheep is an excellent short fat-tailed breed in China. Fat deposition in Hu sheep tail affects carcass quality and consumes a lot of energy, leading to an increase in feed cost. The objective of this study was to analyze the effects of HMGA1 polymorphism on tail fat weight in Hu sheep. Partial coding and non-coding sequences of HMGA1 were amplified with PCR and single nucleotide polymorphisms (SNP) of HMGA1 in 1163 Hu sheep were detected using DNA sequencing and KASPar technology. RT-qPCR analysis was performed to test HMGA1 expression in different tissues. The results showed that the expression of HMGA1 was higher in the duodenum, liver, spleen, kidney, and lung than in the heart, muscle, rumen, tail fat, and lymph. A mutation, g.5312 C > T, was detected in HMGA1; g.5312 C > T was significantly associated with tail fat weight, relative weight of tail fat (body weight), and relative weight of tail fat (carcass) (p < 0.05). The tail fat weight of the TT genotype was remarkably higher than that of the CC and TC genotypes. Therefore, HMGA1 can be used as a genetic marker for marker-assisted selection of tail fat weight in Hu sheep.

Apelin-mediated deamidation of HMGA1 promotes tumorigenesis by enhancing SREBP1 activity and lipid synthesis.

Enhanced fatty acid synthesis provides proliferation and survival advantages for tumor cells. Apelin is an adipokine, which serves as a ligand of G protein-coupled receptors that promote tumor growth in malignant cancers. Here, we confirmed that apelin increased sterol regulatory element-binding protein 1 (SREBP1) activity and induced the expression of glutamine amidotransferase for deamidating high-mobility group A 1 (HMGA1) to promote fatty acid synthesis and proliferation of lung cancer cells. This post-translational modification stabilized the HMGA1 expression and enhanced the formation of the apelin-HMGA1-SREBP1 complex to facilitate SREBP1 activity for lipid metabolism and lung cancer cell growth. We uncovered the pivotal role of apelin-mediated deamidation of HMGA1 in lipid metabolism and tumorigenesis of lung cancer cells.

HMGA1 gene expression level in cancer tissue and blood samples of non-small cell lung cancer (NSCLC) patients: preliminary report.

The study aimed to assess the HMGA1 gene expression level in NSCLC patients and to evaluate its association with selected clinicopathological features and overall survival of patients. The expression of the HMGA1, coding non-histone transcription regulator HMGA1, was previously proved to correlate with the ability of cancer cells to metastasize the advancement of the disease. The prognostic value of the HMGA1 expression level was demonstrated in some neoplasms, e.g., pancreatic, gastric, endometrial, hepatocellular cancer, but the knowledge about its role in non-small cell lung cancer (NSCLC) is still limited. Thus, the HMGA1 expression level was evaluated by real-time PCR method in postoperative tumor tissue and blood samples collected at the time of diagnosis, 100 days and 1 year after surgery from 47 NSCLC patients. Mean HMGA1 expression level in blood decreased systematically from the time of cancer diagnosis to 1 year after surgery. The blood HMGA1 expression level 1 year after surgery was associated with the tobacco smoking status of patients (p= 0.0230). Patients with high blood HMGA1 expression levels measured 100 days after surgery tend to have worse overall survival than those with low expression levels (p= 0.1197). Tumor HMGA1 expression level was associated with neither features nor the overall survival of NSCLC patients. Moreover, no correlation between HMGA1 expression level measured in tumor tissue and blood samples was stated. Blood HMGA1 mRNA level could be a promising factor in the prognostication of non-small cell lung cancer patients.