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N6-methyladenosine (m6A) is capable of mediating circRNA generation in carcinoma biology. Nevertheless, the posttranscriptional systems of m6A and circRNA in hepatocellular carcinoma (HCC) development are still unclear. The present study identified a circRNA with m6A modification, circHPS5, which was increased in neoplasm HCC tissues and indicated poor patient survival. Silencing of circHPS5 inhibited epithelial-mesenchymal transition (EMT) and cancer stem-like cell (CSC) phenotypes. Notably, METTL3 could direct the formation of circHPS5, and specific m6A controlled the accumulation of circHPS5. YTHDC1 facilitated the cytoplasmic output of circHPS5 under m6A modification. In addition, we demonstrated that circHPS5 can act as a miR-370 sponge to regulate the expression of HMGA2 and further accelerate HCC cell tumorigenesis. Accordingly, the m6A modification of circHPS5 was found to modulate cytoplasmic output and increase HMGA2 expression to facilitate HCC development. The new regulatory model of “circHPS5-HMGA2” provides a new perspective for circHPS5 as an important prognostic marker and therapeutic target in HCC and provides mechanistic insight for exploring the carcinogenic mechanism of circHPS5 in HCC., Graphical abstract, m6A modifying process of circHPS5 expedites cytoplasmic output and facilitates the EMT and CSC phenotypes, promoting migrating and proliferating processes pertaining to HCC by acting as one miR-370 sponge to regulate the expressing state of HMGA2.

The lncRNA ZFAS1 plays a carcinogenic regulatory role in many human tumours, but it is rarely reported in pancreatic cancer. We identify the role and molecular mechanisms of ZFAS1 in pancreatic cancer. The expression of ZFAS1, miR-497-5p and HMGA2 in pancreatic cancer tissues was detected by qRT-PCR. Pancreatic cancer data in The Cancer Genome Atlas were also included in this study. CCK8, EdU, transwell and scratch wound assays were used to investigate the biological effects of ZFAS1 in pancreatic cancer cells. MS2-RIP, RNA pull-down, RNA-ChIP and luciferase reporter assays were used to clarify the molecular biological mechanisms of ZFAS1 in pancreatic cancer. The role of ZFAS1 in vivo was also confirmed via xenograft experiments. ZFAS1 was overexpressed in pancreatic cancer tissues. ZFAS1 promoted the growth and metastasis of pancreatic cancer cells, and miR-497-5p acted as a tumour suppressor gene in pancreatic cancer by targeting HMGA2. We also demonstrated that ZFAS1 exerts its effects by promoting HMGA2 expression through decoying miR-497-5p. We also found that ZFAS1 promoted the progression of pancreatic cancer in vivo by modulating the miR-497-5p/HMGA2 axis. In conclusion, this study revealed a new role for and the molecular mechanisms of ZFAS1 in pancreatic cancer, identifying ZFAS1 as a novel target for the diagnosis and treatment of pancreatic cancer.

The development of chemoresistance reduces the efficacy of anti‐cancer drugs. Cervical cancer is still one of the most common cancer types in developing countries. The oncogenic protein high mobility group AT‐hook 2 (HMGA2) is involved in the development and progression of tumors, although its role in chemoresistance of cervical cancer remains unclear. Here, we report that HMGA2 is highly expressed in cervical cancer and negatively correlated with cisplatin‐induced cell death. We performed liquid chromatography‐tandem mass spectrometry to demonstrate that HMGA2 has high potential to interact with casein kinase II A1 (CSNK2A1). Moreover, we observed that HMGA2 co‐localizes with CSNK2A1 in the nucleus by immunofluorescence. Binding of HMGA2‐CSNK2A1 was detected by immunoprecipitation assays. In addition, we identified that cisplatin induces an interaction between CSNK2A1 and HMGA2, thereby promoting the phosphorylation of HMGA2. CX‐4945, a CSNK2A1 inhibitor, could inhibit the phosphorylation of HMGA2 and sensitize tumor cells to cisplatin. Our results reveal that CSNK2A1‐dependent HMGA2 phosphorylation may partially underlie cisplatin‐resistance in cervical cancer, suggesting that HMGA2 phosphorylation may have potential as a predicative biomarker and therapeutic target to improve chemotherapeutic efficacy., The oncogenic protein high mobility group AT‐hook 2 (HMGA2) participates in the development and progression of tumors. Cisplatin may enhance the interaction between HMGA2 and serine‐threonine kinase casein kinase II A1, thereby causing enhancement of HMGA2 phosphorylation in a time‐ and dose‐dependent manner, which in turn affects the bcl‐2/bax pathway and the resistance of cervical cancer cells to cisplatin.

Colon cancer is a common human cancer worldwide. The survival rate of late staged or metastatic colon cancer patients remains low even though the effectiveness of treatment in colon cancer has greatly improved. Research on tumorigenesis mechanisms and discovery of novel molecular target for treating colon cancer is critical. The promotion roles of WHSC1 in multiple myeloma have been demonstrated previously, yet, the regulation of WHSC1 in other cancers is largely unknown, especially in colon cancer. Here, in this study, we analyzed and identified WHSC1 while studying the genetic regulations of HMGA2 in colon cancer cells by microarray analysis, and investigated the HMGA2-WHSC1 interaction. We then applied CRISPR technology to establish stable WHSC1 knockout cells, to address the functional regulation of WHSC1 in colon cancer. In summary, our results for the first time identified the HMGA2-WHSC1 interaction in colon cancer. Moreover, we discovered that WHSC1 promotes cancer proliferation, facilitates resistance of chemotherapy agent, and promotes metastatic capacity of colon cancer.

A genetic polymorphism (rs968697 T > C) in the HMGA2 gene has recently been linked to an increased risk of hepatoblastoma. However, no studies have been conducted to investigate the effect of the polymorphism on the risk of colorectal cancer (CRC). The study aimed to explore whether the rs968697 polymorphism had a significant impact on CRC risk. A total of 500 CRC patients and 500 age and gender matched healthy individuals were genotyped by using the SNaPshot method. Quantitative real-time PCR technology was used to detect the relative expression of the HMGA2 gene in 30 pairs of primary CRC and adjacent non-cancerous tissues. Results: HMGA2 rs968697 polymorphism was significantly associated with CRC risk [CC vs. TT: OR = 0.20, 95%CI = 0.06-0.70, P = 0.01; (CC + CT) vs. TT: OR = 0.71, 95%CI = 0.53-0.96, P = 0.02; CC vs. (CT + TT): OR = 0.21, 95%CI = 0.06-0.73, P = 0.01; C vs. T: OR = 0.67, 95%CI = 0.51-0.89, P < 0.01]. The analysis based on tumor stage indicated that the CRC patients with HMGA2 rs968697 C allele were less likely to have high-stage tumors. Furthermore, the genotype-tissue expression analysis revealed that the rs968697 CC genotype was linked to the low expression of HMGA2 gene. The in silico analysis revealed that the rs968697 polymorphism in the promoter region of the HMGA2 gene could influence transcription factor binding, including ATF6, DBP, CDPCR3, DR3, NRSF, PAX8, PPARA, SZF11, TAXCREB and POLR2A. In conclusion, our findings suggested that the HMGA2 rs968697 polymorphism was linked to CRC risk and could be used as a biomarker to detect CRC risk.

Rhabdomyosarcoma (RMS) encompasses a heterogeneous group of tumors with striated muscle differentiation. RMSs are classified as alveolar, embryonal, spindle cell /sclerosing and pleomorphic types and molecular analysis of these tumors has identified aberrations that are useful in their further subclassification. Spindle cell rhabdomyosarcoma (SpRMS) is uncommon and has been described with VGLL2 fusions, EWSR1/FUS-TFCP2 rearrangements, and myoD1 mutations - the mutations are associated with significantly different prognoses. Also, the NCOA2-MEIS1 fusion gene was recently described in two primary intraosseous RMS that contained spindle cell components. Herein, we report three cases of SpRMS harboring different novel fusion genes, one possessing EP300-VGLL3, a second with NCOA2-MEIS1 and CAV1-MET, and the third case had HMGA2-NEGR1 and multiple amplified genes. This article is protected by copyright. All rights reserved.

Purpose HMGA2 has frequently been found in benign as well as malignant tumors and a significant association between HMGA2 overexpression and poor survival in different malignancies was described. In pancreatic ductal adenocarcinoma (PDAC), nuclear HMGA2 expression is associated with tumor dedifferentiation and presence of lymph node metastasis. Nevertheless, the impact of HMGA2 occurrence in other cell compartments is unknown. Methods Intracellular distribution of HMGA2 was analyzed in PDAC (n = 106) and peritumoral, non-malignant ducts (n = 28) by immunohistochemistry. Findings were correlated with clinico-pathological data. Additionally, intracellular HMGA2 presence was studied by Western blotting of cytoplasmic and nuclear fractions of cultured cells. Results HMGA2 was found in the cytoplasm and in the nucleus of cultured cells. In human tumor tissue, HMGA2 was also frequently found in the cytoplasm and the nucleus of tumor cells, however, nuclear staining was generally stronger. Direct comparison from tumor tissue with corresponding non-neoplastic peritumoral tissue revealed significantly stronger expression in tumors (p = 0.003). Of note, the nuclear staining was significantly stronger in lymph node metastatic cell nuclei compared to primary tumor cell nuclei (p = 0.049). Interestingly, cytoplasmic staining positively correlated with lymph vessel (p = 0.004) and venous invasion (p = 0.046). Conclusion HMGA2 is a prognostic marker in PDAC. Firstly, we found a positive correlation for cytoplasmic HMGA2 expression with lympho-vascular invasion and, secondly, we found a significantly stronger nuclear expression of HMGA2 in cancer-positive lymph node nuclei compared to primary tumor cell nuclei. So far, the role of cytoplasmic HMGA2 is nearly unknown, however, our data lend support to the hypothesis that cytoplasmic HMGA2 expression is involved in nodal spread.

Background Circular RNAs (circRNAs) had been identified as a non‐coding RNA associated with many types of cancer in recent years. However, the involvement of hsa_circ_0008274 in lung adenocarcinoma (LUAD) has not been explored. The aim of our research is to explore the biological mechanism and function of hsa_circ_0008274 in LUAD. Methods The hsa_circ_0008274, miR‐578, and high mobility group AT‐Hook 2 (HMGA2) mRNA expression levels were detected via qRT‐PCR. Cell Counting Kit‐8 (CCK‐8) Transwell assay and wound healing assay were performed to measure the cell proliferation, invasion, and migration ability. Luciferase reporter and Western blotting experiments were performed to characterize the competing endogenous RNA (ceRNA) mechanism of hsa_circ_0008274. Results Our findings determined that the expression of hsa_circ_0008274 in LUAD was significantly decreased. Cell experiments showed that overexpressed hsa_circ_0008274 could reduce the proliferation and invasion ability of LUAD cells. Moreover, miRNA‐578 could identify as a miRNA sponge of hsa_circ_0008274. Overexpressed hsa_circ_0008274 reduced the proliferation and invasion of LUAD cells caused by miR‐578 mimics. Increasing the expression of miR‐578 can aggravate the proliferation and invasion of LUAD cells and block the inhibition of proliferation and invasion of LUAD cells mediated by overexpressed hsa_circ_0008274. Subsequent data indicate that HMGA2 of the tumor‐promoting gene is the target gene of miR‐578. The upregulation of HMGA2 partially reversed the tumor inhibitory effect of LUAD cells induced by overexpressed hsa_circ_0008274 or miR‐578 mimics. Conclusions In summary, our data show that the overexpression of hsa_circ_0008274 repressed the proliferation and invasion of LUAD through downregulating miR‐578 and activating HMGA2., Overexpression of hsa_circ_0008274 repressed the proliferation and invasion of LUAD through downregulating miR‐578 and activating HMGA2.

Cervical cancer is a common female malignancy that is mainly caused by human papillomavirus (HPV) infection. However, the incidence of HPV-negative cervical cancer has shown an increasing trend in recent years. Because the mechanism of HPV-negative cervical cancer development is unclear, this study aims to find the pattern of differential gene expression in HPV-negative cervical cancer and verify the underlying potential mechanism. Differentially expressed genes were compared among HPV-positive cervical cancer, HPV-negative cervical cancer, and normal cervical tissues retrieved from TCGA. Subsequently, dysregulated differentially expressed genes specifically existed in HPV-negative cervical cancer tissues and HPV-negative cell lines were validated by qRT-PCR, western blotting, and immunohistochemical staining. We found seventeen highly expressed genes that were particularly associated with HPV-negative cervical cancer from analysis of TCGA database. Among the 17 novel genes, 7 genes (preferentially expressed antigen in melanoma [PRAME], HMGA2, ETS variant 4 [ETV4], MEX3A, TM7SF2, SLC19A1, and tweety-homologs 3 [TTYH3]) displayed significantly elevated expression in HPV-negative cervical cancer cells and HPV-negative cervical cancer tissues. Additionally, higher expression of MEX3A and TTYH3 was associated with a shorter overall survival of patients with HPV-negative cervical cancer. Our study implies that these seven genes are more likely to provide novel insights into the occurrence and progression of HPV-negative cervical cancer.

Vector-mediated mutagenesis remains a major safety concern for many gene therapy clinical protocols. Indeed, lentiviral-based gene therapy treatments of hematologic disease can result in oligoclonal blood reconstitution in the transduced cell graft. Specifically, clonal expansion of hematopoietic stem cells (HSCs) highly expressing HMGA2, a chromatin architectural factor found in many human cancers, is reported in patients undergoing gene therapy for hematologic diseases, raising concerns about the safety of these integrations. Here, we show for the first time in vivo multilineage and multiclonal expansion of non-human primate HSCs expressing a 3' UTR-truncated version of HMGA2 without evidence of any hematologic malignancy >7 years post-transplantation, which is significantly longer than most non-human gene therapy pre-clinical studies. This expansion is accompanied by an increase in HSC survival, cell cycle activation of downstream progenitors, and changes in gene expression led by the upregulation of IGF2BP2, a mRNA binding regulator of survival and proliferation. Thus, we conclude that prolonged ectopic expression of HMGA2 in hematopoietic progenitors is not sufficient to drive hematologic malignancy and is not an acute safety concern in lentiviral-based gene therapy clinical protocols.

The long non-coding RNA HLA complex P5 (HCP5) is extensively related to cancer chemoresistance, while its function in gastric cancer (GC) has not been well elucidated yet. Here, the role and mechanism of HCP5 in regulating the chemoresistance of GC to cisplatin (DDP) was investigated. Our results revealed that HCP5 was increased in GC patients and indicated a poor prognosis. HCP5 knockdown weakens DDP resistance and reduced apoptosis of GC cells. miR-128 was decreased in GC patients and sponged by HCP5. HMGA2 was targeted by miR-128 and was increased in GC patients. HCP5 aggravated the resistance of GC cells to DDP in vitro by elevating HMGA2 expression via sponging miR-128. HCP5 silencing inhibited GC cells growth, resistance to DDP, and Ki-67 expression in vivo. In summary, HCP5 contributed to DDP resistance in GC cells through miR-128/HMGA2 axis, providing a promising therapeutic target for GC chemoresistance.

Circular RNA (circRNA) is a new class of non-coding RNA. It was reported that circRNA involves in the metastasis of cancer. The aim of this study is to explore the role and mechanism of circRNA hsa_circ_0062019 in the development of prostate cancer (PCa). Our results showed that hsa_circ_0062019 was highly expressed in PCa cell lines. Cell Counting Kit-8 assay revealed that upregulation of hsa_circ_0062019 boosted PCa cell proliferation, and silencing of hsa_circ_0062019 inhibited cell proliferation. Meanwhile, transwell assay proved that upregulation of hsa_circ_0062019 facilitated PCa cell invasion and migration, while downregulation of hsa_circ_0062019 inhibited these malignant phenotypes. Furthermore, luciferase reporter assay proved the binding of hsa_circ_0062019 with miR-195-5p and the binding between miR-195-5p and high mobility group AT-hook 2 (HMGA2), suggesting that hsa_circ_0062019 promoted the expression of HMGA2 by sponging miR-195-5p. In addition, our results revealed that the hsa_circ_0062019-induced PCa cell malignant phenotypes were notably reversed by the downregulation of HMGA2. Overall, our study demonstrated that hsa_circ_0062019 promoted PCa cell proliferation, migration, and invasion via upregulation of HMGA2 expression by sponging miR-195-5p. Our study proved a novel molecular mechanism of PCa development and provided a potential target for the treatment of PCa.

Background Diagnosis of minor salivary gland (MSG) tumours is often difficult, due to the scarce tissue obtained from bioptic excision and complex histopathological differential diagnosis. In our study we performed an immunohistochemical analysis of PLAG1, HMGA1 and HMGA2 on a series of MSG tumours, in order to develop a new helpful diagnostic panel. Methods A retrospective series of 17 surgical specimens of MSG tumours were analysed for the expression of PLAG1, HMGA1 and HMGA2. Three control cases were enrolled and analysed. An intensity and percentage-based approach was performed, creating a combined score panel. Results PLAG1 facilitate the diagnosis of benign tumours, discriminating it from malignant histotypes, with a defined cut-off value. Similarly, HMGA1 is significantly higher in benign histotypes than in malignant ones. HMGA2 in our series, did not reveal any association in identifying benign from malignant histotypes. Conclusions In this study we assessed the diagnostic role of PLAG1, HMGA1 and HMGA2 immunohistochemical analysis. The score panel facilitate histopathological diagnosis of these rare tumours, helping to distinguish benign tumours from malignant ones and ameliorating the differential diagnosis of specific histotypes.

Jingying Zhou,1 Pan Wang,1 Ran Zhang,2 Xiaokai Huang,1 Hanqi Dai,1 Li Yuan,3 Jichen Ruan1 1Department of Hematology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang, People’s Republic of China; 2Sydney School of Public Health, The University of Sydney, Camperdown, Sydney, NSW, 2006, Australia; 3Department of Pathology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, 510623, Guangdong, People’s Republic of ChinaCorrespondence: Jichen RuanDepartment of Hematology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, 109 West Xueyuan Road, Wenzhou, 325027, Zhejiang, People’s Republic of ChinaEmail delcruanjichen@163.comLi YuanDepartment of Pathology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, 9 Jinsui Road, Guangzhou, 510623, Guangdong, People’s Republic of ChinaEmail lizzyklarck@126.comBackground: Glioma is a malignant central nervous system tumor in children, with poor outcomes and prognosis. HMGA2 is a proto-oncogene with increased expression in various malignancies.Methods: We explored the association of HMGA2 polymorphisms with glioma susceptibility in Chinese children using a case-control study (191 cases, 248 controls). HMGA2 single nucleotide polymorphisms (rs6581658 A>G; rs8756 A>C; rs968697 T>C) were genotyped using PCR-based TaqMan.Results: Increased glioma susceptibility was associated with rs6581658 A>G; AG (adjusted odds ratio (OR) = 1.71, 95% confidence interval (CI) = 1.13– 2.58, P = 0.010) or GG (adjusted OR = 3.12, 95% CI = 1.26– 7.74, P = 0.014) genotype carriers had significantly raised glioma risk compared with AA genotype carriers. The rs6581658 AG/GG (adjusted OR = 1.85, 95% CI = 1.25– 2.73, P = 0.002) and AA/GG (adjusted OR = 2.58, 95% CI = 1.05– 6.33, P = 0.038) genotypes were associated with an increased risk of glioma relative to the AA genotype. Subjects with 2– 3 risk genotypes had a significantly elevated risk (adjusted OR = 1.93, 95% CI = 1.31– 2.84, P = 0.001) relative to those with 0– 1 risk genotype.Conclusion: HMGA2 rs6581658 A>G is associated with glioma susceptibility in Chinese children.Keywords: HMGA2, polymorphism, susceptibility, glioma

Background: Locoregional spread is a frequent finding in oral cancer which dictates poor prognosis. HMGA2 expression has been linked to malignant traits of oral cancer in tissue biopsies however, data on HMGA2 expression in liquid biopsies in oral cancer is sparse. Purpose of this study was to explore prognostic relevance of HMGA2 in liquid biopsies of oral cancer patients. Patients and Methods: After obtaining approval from Institutional Review Board of Ziauddin University and informed written consent from study subjects, expression of circulating HMGA2 was evaluated in 96 OSCC cases and 100 age and sex matched controls via real time PCR using specific set of primers. We further analyzed relationship of various sociodemographic and clinicopathological variables with HMGA2expression and explored its prognostic potential. Results: Expression was seen in 22 (23%) cases. A higher expression was observed among subjects with local invasion (52.6% vs 47.4 %), distant metastasis (71.4% vs 28.6%) and tumor recurrence (57.1% vs 42.9%) p

Background Extrahepatic cholangiocarcinoma requires invasive surgery and is associated with poor prognosis; thus, a prognostic biomarker is highly needed. Extrahepatic cholangiocarcinoma is sub-classified into two types based on their location, namely perihilar and distal. Perihilar cholangiocarcinoma requires lobectomy as curative surgical resection, whereas the distal requires pancreatoduodenectomy. HMGA2 overexpression is reported to correlate with progression, aggressiveness, dissemination and poor prognosis in several types of cancers. Although its association with extrahepatic cholangiocarcinoma has been reported, none of the previous studies assessed its significance in each subtype. Methods We assessed the expression of HMGA2 protein in surgical specimens after curative intent surgery in 80 patients including 41 with perihilar cholangiocarcinoma and 39 with distal cholangiocarcinoma by immunohistochemistry. We then examined its association with clinicopathological findings and patient survival outcomes. Results We found that HMGA2 was expressed in 51% (21 of 41) of perihilar cholangiocarcinoma and 41% (16 of 39) of distal cholangiocarcinoma samples. In perihilar cholangiocarcinoma, we found significant correlations between expression and vascular invasion and perineural invasion. In distal cholangiocarcinoma, we found that protein levels correlated with tumor grade. Univariate and multivariate analyses demonstrated that HMGA2 expression was an independent poor prognostic factor for patients with both subtypes of disease. Conclusions Our results revealed that HMGA2 expression as an independent prognostic marker for both perihilar and distal cholangiocarcinoma that were resected with curative intent.

Introduction: Obesity is a main global health issue and an outstanding cause of morbidity and mortality. Exploring miRNA profiling may help further studies on obesity. Methods: Three morbidly obese and 5 normal-weight Chinese women were enrolled in the microarray testing group. Abdominal subcutaneous adipose tissue (SAT) samples were excised. Total RNAs including miRNAs were extracted. Affymetrix GeneChip miRNA 4.0 Array was used to compare the expression profiles of miRNAs between the 2 groups. Two algorithms, miRanda and TargetScan, were used to predict target messenger RNAs (mRNAs). Bioinformatics analysis was then done based on the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The sample sizes were further expanded to 8 morbidly obese and 9 normal-weight subjects, and quantitative real-time PCR (qRT-PCR) was utilized to verify the expression of differential miRNAs and target genes. Results: As per the microarray assay, 58 miRNAs were differentially expressed in the SAT from the morbidly obese and normal-weight groups (Fold >4, p < 0.01, FDR HMGA2), a target gene of the downregulated miRNA let-7a-5p, was first found to be upregulated 3.19-fold in the SAT of morbidly obese Chinese women when compared to normal-weight controls. Conclusions: MiRNA downregulation is a hallmark of intact SAT in a morbidly obese state. Transcription (DNA-dependent), small-molecule metabolic processes, the MAPK signaling pathway, and cancer-related pathways may play important roles in the occurrence and development of obesity. For the first time, we proved that HMGA2, a target gene of let-7a-5p, is upregulated in the SAT of morbidly obese Chinese women.

Introduction.The main method of preoperative diagnosis of thyroid tumors and the identification of possible metastasis is a cytological examination of smears obtained by fine-needle aspiration biopsy. However, the cytological material of the lymph nodes may not be adequate, and the detection of metastases faces a number of difficulties. In our recent study, we described a variant of the molecular classifier that allows the detection and typing of malignant thyroid tumors by analyzing several molecular markers in cytological preparations.The study objectivewas to assess the applicability of the developed method for the preoperative detection of metastases of papillary and medullary thyroid cancer in the lymph nodes of the neck lateral cellular tissue.Materials and methods.A total of 86 cytological samples were used, obtained from individual lymph nodes of 62 patients who had a diagnosis – thyroid cancer. Samples were analyzed by real-time polymerase chain reaction regarding the preselected set of molecular markers: the BRAF V600E mutation, the normalized concentration of HMGA2, FN1 and SERPINA1 mRNA, 5 miRNAs and the mitochondrial/nuclear DNA ratio. The decision tree-based classifier was used to discriminate between benign and malignant samples.Results.The previously described classifier, based on the analysis of the BRAF V600E mutation, the content of HMGA2 mRNA, 3 miRNAs and the mitochondrial/nuclear DNA ratio, revealed metastases of thyroid cancer with good specificity (98 %) but less sensitivity (83 %). Therefore, a new classifier was built, including three markers – HMGA2 and FN1 mRNA, and miRNA-375, which, with regard to the detection of metastases, showed good sensitivity – 93 % with a slight decrease in specificity (up to 96 %).Conclusion.Thus, we demonstrated the possibility of preoperative detection of thyroid cancer metastases in the lymph nodes of the neck lateral cellular tissue by analyzing several molecular markers in cytological material.

Graphical abstract, Motivation: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease, 2019; COVID-19) is associated with adverse outcomes in patients. It has been observed that lethality seems to be related to the age of patients. While ageing has been extensively demonstrated to be accompanied by some modifications at the gene expression level, a possible link with COVID-19 manifestation still need to be investigated at the molecular level. Objectives: This study aims to shed out light on a possible link between the increased COVID-19 lethality and the molecular changes that occur in elderly people. Methods: We considered public datasets of ageing-related genes and their expression at the tissue level. We selected human proteins interacting with viral ones that are known to be related to the ageing process. Finally, we investigated changes in the expression level of coding genes at the tissue, gender and age level. Results: We observed a significant intersection between some SARS-CoV-2 interactors and ageing-related genes, suggesting that those genes are particularly affected by COVID-19 infection. Our analysis evidenced that virus infection particularly involves ageing molecular mechanisms centred around proteins EEF2, NPM1, HMGA1, HMGA2, APEX1, CHEK1, PRKDC, and GPX4. We found that HMGA1 and NPM1 have different expressions in the lung of males, while HMGA1, APEX1, CHEK1, EEF2, and NPM1 present changes in expression in males due to ageing effects. Conclusion: Our study generated a mechanistic framework to clarify the correlation between COVID-19 incidence in elderly patients and molecular mechanisms of ageing. We also provide testable hypotheses for future investigation and pharmacological solutions tailored to specific age ranges.

Bladder cancer is a common malignant tumor with a high recurrence rate and mortality, while the detailed mechanisms for bladder cancer progression and metastasis are unknown. Recently, long non-coding RNAs (lncRNAs) have been reported to be involved in the development of cancers. In this study, we aim to investigate the role of lncRNA LINC00355 in bladder cancer progression and metastasis. The association between LINC00355 and the prognosis of bladder cancer patients was determined by Kaplan-Meier survival analysis. Cell migration and invasion ability were detected using the Transwell migration and invasion assay. The relationships of LINC00355, miR-424-5p, and High Mobility Group AT-Hook 2 (HMGA2) were verified through the luciferase assay and RNA pull-down assay. Xenograft tumor was established to evaluate tumor lung metastasis in vivo. qRT-PCR and western blot were used to detect gene expression. LINC00355 was upregulated in bladder cancer patients, especially in patients with higher TNM stage. Elevated LINC00355 was correlated with the poor prognosis of bladder cancer patients. Besides, overexpressed LINC00355 promoted migration, invasion, and epithelial-mesenchymal transition (EMT) ability of bladder cancer cells. Contrarily, decreased LINC00355 suppressed migration, invasion, and EMT ability of bladder cancer cells, and lung metastasis of xenograft tumors. Furthermore, LINC00355 could regulate HMGA2 expression by acting as a sponge for miR-424-5p. Overexpression of HMGA2 induced EMT of bladder cancer cells. Additionally, LINC00355 regulated the migration, invasion, and EMT ability of bladder cancer cells through modulating HMGA2 expression via sponging miR-424-5p. LINC00355 promoted migration, invasion, and EMT ability of bladder cancer through elevating HMGA2 expression via acting as a sponge for miR-424-5p.

Our previous studies have shown that MCF-7 breast cancer cell line exposed to 6 Gy and allowed to recover for 7 days (D7-6G) developed radio-resistance. In this study, we have tested the ability of these cells to form tumors in severe combined immunodeficiency (SCID) mice and characterized these tumors by proteomic analyses. Untreated (MCF-C) and D7-6G cells (MCF-R) were injected s.c. in SCID mice and tumor growth monitored. On Day 18, the mice were killed and tumor tissues were fixed in formalin or RNA later. Expression of genes was assessed by reverse transcription-polymerase chain reaction and proteins by enzyme-linked immunosorbent assay/antibody labeling and flow cytometry. Label free proteomic analyses was carried out by liquid chromatography-mass spectrometry. Metabolic analysis was carried out using Seahorse analyzer. MCF-R cells had a shorter latency and formed larger tumors. These tumors were characterized by an increased expression of transforming growth factor β (TGF-β) isoforms; its downstream genes pSMAD3, Snail-1, Zeb-1, HMGA2; hybrid epithelial/mesenchymal phenotype; migration, enrichment of cancer stem cells and radioresistance following challenge dose of radiation. Proteomic analysis of MCF-7R tumors resulted in identification of a total of 649 differentially expressed proteins and pathway analyses using protein annotation through evolutionary relationship indicated enrichment of genes involved in metabolism. Data are available via ProteomeXchange with identifier PXD022506. Seahorse analyzer confirmed increased metabolism in these cells with increased oxidative phosphorylation as well as glycolysis. Increased uptake of 2-NBDG further confirmed increased glycolysis. In summary, we demonstrate that radioresistant breast cancer cells had an enrichment of TGF-β signaling and increased metabolism.

High-mobility group AT-hook2 (HMGA2), serving as an architectural transcription factor, participates in plenty of biological processes. Our study is aimed at illustrating the effect of HMGA2 on hypoxia-induced HUVEC injury and the underlying mechanism. To induce hypoxia-related cell injury, HUVECs were exposed to hypoxic condition for 12–24 h. Molecular expression was determined by Western blot analysis, real-time PCR and immunofluorescence staining. Cell migration was monitored by wound healing assay and Transwell chamber assay. Cell proliferation and apoptosis were measured by MTT assay kits and TUNEL staining. In this study, we discovered that HMGA2 was upregulated in hypoxia-induced HUVECs. Overexpression of HMGA2 promoted cell migration, decreased the apoptosis ratio in response to hypoxia stimulation, while HMGA2 knockdown inhibited cell migration and accelerated apoptosis in HUVECs under hypoxic condition. Mechanistically, we found that HMGA2 induced increased expression of HIF-1α,VEGF, eNOS and AKT. eNOS knockdown significantly reduced HMGA2-mediated pro-migration effects, and AKT knockdown strikingly counteracted HMGA2-mediated anti-apoptotic effect. Hence, our data indicated that HMGA2 promoted cell migration by regulating HIF-1α/VGEF/eNOS signaling and prevented cell apoptosis by activating HIF-1α/VGEF/AKT signaling in HUVECs.

Background The role of high mobility group A2 (HMGA2) in the progression of hepatocellular carcinoma (HCC) is yet to be investigated, though tumor-associated macrophages (TAMs) are known to mediate the process. Methods Immunohistochemistry (IHC), Western blot, and real-time PCR assays were performed to identify HMGA2 and TAMs markers. The TAMs-like macrophages (TAMs-Mφs) were triggered with the help of 25 ng/mL hM-CSF and 50% NBCM. EdU assay wound healing assay, transwell assay, and TUNEL assay, as well as flow cytometry, were carried out to study the effect of HMGA2 or TAMs on the functioning of HCC cells. Results HCC tumor tissues were detected with upregulated HMGA2 and TAMs markers (CD68, CD163, and CD204); in addition, HMGA2 was positively correlated with TAMs markers. The proliferation, migration, and invasion of HepG2 cells were also observed to be stimulated by HMGA2. Remarkably, cell apoptosis was not affected by upregulated HMGA2, but HMAG2 inhibition was observed to intensify it. Also, the release of CSF1 was observed to be amplified by HMGA2. HMGA2-overexpressed-HepG2 cells promoted the migrating abilities of both M0-Mφs and TAMs-Mφs but were suppressed by HMGA2 down-regulated HepG2 cells. In addition, TAMs-Mφs supernatant regulated the CCAT1/let-7b/HMGA2 signaling pathway by intensifying the malignant biological behaviors. Conclusion HMGA2 stimulated TAMs-induced HCC progression, mediated by the CCAT1/let-7b/HMGA2 signaling pathway, TAMs aggravated HCC development.

Lipomas are benign soft tissue fatty tumours that most commonly appear in the third decade of life when fatty tissue accumulates. Histologically, lipoma is composed of mature fat cells with a thin fibrous capsule. Simple lipomas account for 80% of adipose tissue tumours. The aetiology may be genetic like Familial Multiple Lipomatosis. Some tumours, like the well differentiated Liposarcomas never metastasize unless they undergo de-differentiation. They can be introduced as Atypical Lipomatous Tissue, ALT. Southern blot analysis is performed by obtaining DNA from ALT, cases in which most of them are characterized by the presence of supernumerary ring and long marker chromosomes. The complex chromosome region contains genes MDM2, CDK4, HMGI- C, SAS, GLI, CHOP, OS4 and OSP. Most of ALTs, after analysis revealed amplification of CDK4 and MDM2 proto- oncogenes that play major role in permitting over ride of block operated on cell proliferation. Immuno-histochemical results have shown MDM2 over expression in about 50% of ALTs along with weak CDK4 immuno-positivity. Also the lipomas with Gene fusion transcripts have the expression of certain genes, HMGA2/LPP, HMGA2/RDCI and HMGA2/NFIB. Of these 98% of cases were analyzed for the possible expression of HMGA2/LPP and LPP- HMGA2 fusion genes using reverse transcription polymerase chain reaction. Over all these cases, shows non-enhanced adipocyte apoptosis and enhanced adipogenesis in lipoma tissue. Thus studies provide insights into molecular pathogenesis of lipomatous tumour and representation of distinctive subset of mesenchymal neoplasms with mature adipocyte differentiation.

The mammalian high mobility group protein AT-hook 2 (HMGA2) is a multi-functional DNA-binding protein that plays important roles in tumorigenesis and adipogenesis. Previous results showed that HMGA2 is a potential therapeutic target of anticancer and anti-obesity drugs by inhibiting its DNA-binding activities. Here we report the development of a miniaturized, automated AlphaScreen ultra-high-throughput screening assay to identify inhibitors targeting HMGA2-DNA interactions. After screening the LOPAC1280 compound library, we identified several compounds that strongly inhibit HMGA2-DNA interactions including suramin, a century-old, negatively charged antiparasitic drug. Our results show that the inhibition is likely through suramin binding to the “AT-hook” DNA-binding motifs and therefore preventing HMGA2 from binding to the minor groove of AT-rich DNA sequences. Since HMGA1 proteins also carry multiple “AT-hook” DNA-binding motifs, suramin is expected to inhibit HMGA1-DNA interactions as well. Biochemical and biophysical studies show that charge-charge interactions and hydrogen bonding between the suramin sulfonated groups and Arg/Lys residues play critical roles in the binding of suramin to the “AT-hook” DNA-binding motifs. Furthermore, our results suggest that HMGA2 may be one of suramin’s cellular targets.

Background Elucidation of lipid metabolism and accumulation mechanisms is of paramount importance to understanding obesity and unveiling therapeutic targets. In vitro cell models have been extensively used for these purposes, yet, they do not entirely reflect the in vivo setup. Conventional lipomas, characterized by the presence of mature adipocytes and increased adipogenesis, could overcome the drawbacks of cell cultures. Also, they have the unique advantage of easily accessible matched controls in the form of subcutaneous adipose tissue (SAT) from the same individual. We aimed to determine whether lipomas are a good model to understand lipid accumulation. Methods We histologically compared lipomas and control SAT, followed by assessment of the lipidome using high-resolution 1H NMR spectroscopy and ESI-IT mass spectrometry. RNA-sequencing was used to obtain the transcriptome of lipomas and the matched SAT. Results We found a significant increase of small-size (maximal axis 150 µm) adipocytes within lipomas. This suggests both enhanced adipocyte proliferation and increased lipid accumulation. We further show that there is no significant change in the lipid composition compared to matched SAT. To better delineate the pathophysiology of lipid accumulation, we considered two groups with different genetic backgrounds: (1) lipomas with HMGA2 fusions and (2) without gene fusions. To reduce the search space for genes that are relevant for lipid pathophysiology, we focused on the overlapping differentially expressed (DE) genes between the two groups. Gene Ontology analysis revealed that DE genes are enriched in pathways related to lipid accumulation. Conclusions We show that the common shared lipid accumulation mechanism in lipoma is a reduction in lipolysis, with most gene dysregulations leading to a reduced cAMP in the adipocyte. Superficial lipomas could thus be used as a model for lipid accumulation through altered lipolysis as found in obese patients.

Background Endometrial cancer (EC) is one of the most common gynecological malignancies. Circular RNAs (circRNAs) play crucial roles in the occurrence and development of tumors. This research aimed to explore the function and potential mechanism of human serum albumin (hsa)_circ_0109046 in EC. Materials and Methods The abundance of circ_0109046, microRNA-136 (miR-136) and high-mobility group AT-hook 2 (HMGA2) was detected by quantitative real-time polymerase chain reaction or Western blot. Cell counting kit-8 (CCK-8) and colony formation assays were employed to assess cell proliferation. Transwell assay was used to measure cell migration and invasion. The levels of E-cadherin, Vimentin and N-cadherin were examined by Western blot. The binding association among circ_0109046, miR-136 and HMGA2 was verified by dual-luciferase reporter assay, RNA pull-down assay and RNA immunoprecipitation assay. Xenograft assay was performed to test tumor growth in vivo. Results Circ_0109046 and HMGA2 were up-regulated, and miR-136 was down-regulated in EC tissues and cells. Knockdown of circ_0109046 impeded the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of EC cells. Moreover, miR-136 knockdown reversed the suppression of circ_0109046 silencing on EC development. HMGA2 overexpression abolished the inhibition of miR-136 on EC progression. Besides, depletion of circ_0109046 inhibited EC growth in vivo. Conclusion Circ_0109046 accelerated EC progression via modulating miR-136/HMGA2 axis, indicating that circ_0109046 might be a promising therapeutic target for EC.

Numerous studies have implicated changes in the Y chromosome in male cancers, yet few have investigated the biological importance of Y chromosome noncoding RNA. Here we identify a group of Y chromosome–expressed long noncoding RNA (lncRNA) that are involved in male non–small cell lung cancer (NSCLC) radiation sensitivity. Radiosensitive male NSCLC cell lines demonstrated a dose-dependent induction of linc-SPRY3-2/3/4 following irradiation, which was not observed in radioresistant male NSCLC cell lines. Cytogenetics revealed the loss of chromosome Y (LOY) in the radioresistant male NSCLC cell lines. Gain- and loss-of-function experiments indicated that linc-SPRY3-2/3/4 transcripts affect cell viability and apoptosis. Computational prediction of RNA binding proteins (RBP) motifs and UV-cross-linking and immunoprecipitation (CLIP) assays identified IGF2BP3, an RBP involved in mRNA stability, as a binding partner for linc-SPRY3-2/3/4 RNA. The presence of linc-SPRY3-2/3/4 reduced the half-life of known IGF2BP3 binding mRNA, such as the antiapoptotic HMGA2 mRNA, as well as the oncogenic c-MYC mRNA. Assessment of Y chromosome in NSCLC tissue microarrays and expression of linc-SPRY3-2/3/4 in NSCLC RNA-seq and microarray data revealed a negative correlation between the loss of the Y chromosome or linc-SPRY3-2/3/4 and overall survival. Thus, linc-SPRY3-2/3/4 expression and LOY could represent an important marker of radiotherapy in NSCLC.Significance:This study describes previously unknown Y chromosome–expressed lncRNA regulators of radiation response in male NSCLC and show a correlation between loss of chromosome Y and radioresistance.

Background Colorectal cancer is one of the three most common cancers worldwide. Altered TGF-β signaling pathway in colorectal cancer is associated with metastasis and poor prognosis. It is also involved in epithelial-to-mesenchymal transition (EMT), which is essential in progression and metastasis. This study aims to investigate the role of transgelin (TAGLN) and high-mobility group AT-hook 2 (HMGA2) in the progression of colon cancer. Methods HT29 and HCT116 cells were treated with TGF-β, and the effects of inhibition of TAGLN and overexpression of HMGA2 on TGF-β treated cell on cell migration and invasion, expression of EMT markers, including E-cadherin, vimentin and fibronectin were detected as well as MMP2 and MMP9, which are critical in cancer cell metastasis. The interaction of TAGLN and HMGA2 was also investigated by using co-immunoprecipitation. The function of TAGLN in tumor metastasis and growth was investigated in vivo. Results We found that TGF-β could significantly promote the migration of HT29 and HCT116 cells, as well as TAGLN protein expression and nucleus translocation, while inhibition of TAGLN could effectively reverse the effects of TGF-β on HT29 and HCT116 cells, which was observed in terms of decreased cell migration and invasion. Knockdown of TAGLN could also rescue TGF-β-induced loss of E-cadherin, and decreased TGF-β-induced vimentin and fibronectin expression; the elevation of MMP9 and MMP2 was also reversed by inhibition of TAGLN. Further investigation confirmed the interaction of HMGA2 and TAGLN, as overexpression of HMGA2 restores the effects of TGF-β on HT29 cells, which were attenuated by TAGLN inhibition both in vitro and in vivo. Conclusion Overall, our study revealed that interaction between TAGLN and HMGA2 was involved in TGF-β-induced cell migration and promotion of colon cancer cells, suggesting that HMGA2 and TAGLN are potential molecular targets to prevent colon cancer progression.

Tendon-derived stem cells (TSCs) play a primary role in tendon physiology, pathology, as well as tendon repair and regeneration after injury. TSCs are often exposed to mechanical loading-related cellular stresses such as oxidative stress, resulting in loss of stemness and multipotent differentiation potential. Cytoprotective autophagy has previously been identified as an important mechanism to protect human TSCs (hTSCs) from oxidative stress induced impairments. In this study, we found that high-mobility AT-hook 2 (HMGA2) overexpression protects hTSCs against H2O2-induced loss of stemness through autophagy activation. Evidentially, H2O2 treatment increases the expression of Nudt21, a protein critical to polyadenylation site selection in alternative polyadenylation (APA) of mRNA transcripts. This leads to increased cleavage and polyadenylation of HMGA2 3′-UTR at the distal site, resulting in increased HMGA2 silencing by the microRNA let-7 and reduced HMGA2 expression. In conclusion, Nudt21-regulated APA of HMGA2 3′-UTR and subsequent HMGA2 downregulation mediates oxidative stress induced hTSC impairments.

The high mobility group AT-hook 2 (HMGA2) gene encodes a transcription factor that is expressed during embryonic development but down-regulated in adult tissues. Its re-expression in adult tissues is often associated with tumorigenesis. In this study, we found that HMGA2 is highly expressed in human cutaneous squamous cell carcinoma (SCC) cell lines and primary SCC tumors, but not in adjacent normal skin. In non-ultraviolet (UV)-irradiated mouse skin, baseline Hmga2 expression was detected in the epidermis but not in hair follicles. Following chronic UV exposure, we found activation of Hmga2 in hair follicles. UV-induced mouse skin SCC tumors displayed a ubiquitous increase in Hmga2 expression compared to non-tumor bearing adjacent skin. In human SCC cells, decreased HMGA2 expression was linked with reduced cell proliferation following depletion of FOXM1 and TRIP13, two UV master regulator genes. Taken together, these findings highlight an important biomarker function of HMGA2 expression in UV-induced skin tumorigenesis and cell proliferation.

In this study, we identified a circular form of ASPH RNA (circASPH), expression of which was upregulated in lung adenocarcinoma and the human lung adenocarcinoma cell lines. We also found a positive correlation between circASPH level and the T and N stages of lung adenocarcinoma patients. Patients with higher levels of circASPH had a shorter overall survival. Moreover, we demonstrated that circASPH was directly regulated by HMGA2 and Twist1. The direct positive regulation of circASPH by Twist1 was dependent on the presence of HMGA2. Functional assays indicated that circASPH promoted the proliferation, migration, and invasion of lung adenocarcinoma cell lines in vitro. The promoting effect of tumor growth by circASPH was also observed in vivo. Mechanistically, circASPH was identified to act as a molecular sponge for miR-370 and abrogate miR-370-mediated inhibition of HMGA2. Finally, we demonstrated that the oncogenic function of circASPH was HMGA2-dependent. These findings reveal the oncogenic functions of the HMGA2-circASPH-HMGA2 axis and may be useful in developing circRNA-based therapeutic strategies for lung adenocarcinoma.

Increasing evidence shows that aberrant lncRNAs expression contributes to the progression of gastric cancer (GC). The role of the novel lncRNA OIP5-AS1 and its underlying mechanisms in the growth of GC is largely unknown. Here we demonstrate for the first time that OIP5-AS1 expression was up-regulated in GC tissues and cell lines, which significantly correlated with unfavorable clinical characteristics and shorter survival. The results of in vitro and in vivo gain- and loss-of-function experiments indicate that OIP5-AS1 promoted cell proliferation and colony formation while inhibiting apoptosis of GC cells. OIP5-AS1 functioned as an endogenous sponge for miR-367-3p in GC cells. Restoration of miR-367-3p expression abolished the biological effects of OIP5-AS1 on GC cells. Moreover, we show that HMGA2 was a downstream target of miR-367-3p and mediated the effects of OIP5-AS1 on GC cells. OIP5-AS1 regulated the activities of the PI3K/AKT and Wnt/β-catenin pathways through HMGA2. In conclusion, OIP5-AS1 functions as an oncogenic lncRNA that promotes the progression of GC and may serve as a therapeutic target for managing GC.

Pancreatic ductal adenocarcinoma (PDAC) lethality is due to metastatic dissemination. Characterization of rare, heterogeneous circulating tumor cells (CTCs) can provide insight into metastasis and guide development of novel therapies. Using the CTC-iChip to purify CTCs from PDAC patients for RNA-seq characterization, we identify three major correlated gene sets, with stemness genes LIN28B/KLF4, WNT5A, and LGALS3 enriched in each correlated gene set; only LIN28B CTC expression was prognostic. CRISPR knockout of LIN28B—an oncofetal RNA-binding protein exerting diverse effects via negative regulation of let-7 miRNAs and other RNA targets—in cell and animal models confers a less aggressive/metastatic phenotype. This correlates with de-repression of let-7 miRNAs and is mimicked by silencing of downstream let-7 target HMGA2 or chemical inhibition of LIN28B/let-7 binding. Molecular characterization of CTCs provides a unique opportunity to correlated gene set metastatic profiles, identify drivers of dissemination, and develop therapies targeting the “seeds” of metastasis., Metastatic dissemination contributes to the lethality in pancreatic ductal adenocarcinoma (PDAC). Here, the authors perform RNA-sequencing on patient derived circulating tumor cells (CTCs) and identify three major CTC subgroups, and show the therapeutic potential of targeting LIN28B/let-7 pathway to halt cancer metastasis.

Aims Meningeal chondromas constitute a small fraction of central nervous system tumors, with only 61 cases reported in the literature. Somatic mutations of IDH1/2 genes have been described in enchondromas, and, in soft-tissue chondromas, rearrangements of the HMGA2 gene have been reported. The aim of our study was to perform molecular analyses of 3 additional cases and to do a complete review of the literature to better characterize this rare entity. Materials and methods Here, we report 3 cases of primitive meningeal chondromas in children and young adults. Immunohistochemical analyses for HMGA2 and IDH1R132H, molecular analyses of IDH1/2 mutations, and FISH analysis of the HMGA2 locus were performed. Results Immunohistochemical analyses of all cases were negative for IDH1R132H and HMGA2 proteins. Molecular analyses failed to reveal IDH1/2 mutations, and FISH analyses did not evidence any HMGA2 rearrangements. Similarly to what is reported in the literature, the 3 meningeal chondromas in this study were benign tumors with no recurrence after complete resection with a follow-up of 85, 46, and 89 months. Conclusion Meningeal chondroma is rare. It affects predominantly young adults and has a good outcome. No molecular alterations have currently been described in this entity.

Introduction Intravenous leiomyomatosis (IVL) is currently regarded as a special variant of the common uterine leiomyoma (LM). Though IVL shows a similar histological morphology to LM, IVL is characterized by unique intravenous growth patterns and low‐grade malignant potential, which are quite different from LM. There are currently few studies underlying the molecular alterations of IVL, though this information is important for understanding the pathogenesis of the disease, and for identifying potential biomarkers. Method We carried out a high‐throughput whole transcriptome sequencing of tumor and normal tissue samples from five IVL patients and five LM patients and compared the differentially expressed genes (DEGs) between IVL and leiomyoma. We performed multiple different enrichment and target analyses, and the expression of selected DEGs was validated using RT‐qPCR in formalin‐fixed samples. Results Our study identified substantial different genes and pathways between IVL and LM, and functional enrichment analyses found several important pathways, such as angiogenesis and antiapoptosis pathways, as well as important related genes, including SH2D2A, VASH2, ADAM8, GATA2, TNF, and the lncRNA GATA6‐AS1, as being significantly different between IVL and LM (P = .0024, P = .0195, P = .0212, P = .0435, P = .0401, and P = .0246, respectively). CXCL8, LIF, CDKN2A, BCL2A1, COL2A1, IGF1, and HMGA2 were also differently expressed between IVL and LM groups, but showed no statistical difference (P = .2409, P = .1773, P = .0596, P = .2737, P = .1553, P = .1045, and P = .1847, respectively) due to the large differences among individuals. Furthermore, RT‐qPCR results for five selected DEGs in IVL tissues and adjacent nontumor tissues were mainly consistent with our sequencing results. Conclusion Our results indicated that IVL may be a solid entity that is unique and different from LM, proving consistent with previous studies. Furthermore, we identified DEGs, particularly within angiogenesis and antiapoptosis pathway‐related genes that may play crucial roles in the development and pathogenesis of IVL and may be potential specific biomarkers., A transcriptome sequencing on tumor and normal samples from five IVL patients and five LM patients was performed. Angiogenesis and antiapoptosis pathways, and some important genes, and lncRNA are vastly different between IVL and LM, with RT‐qPCR validation. The result suggests that IVL is a solid entity different from LM in the development and pathogenesis.

Malignant peripheral nerve sheath tumours (MPNSTs) are highly aggressive Schwann cell-derived sarcomas, and they are either associated with neurofibromatosis type 1 (NF1) or sporadic. Our previous study found that high mobility group protein A2 (HMGA2) regulates NF1-MPNST growth through Musashi-2 (MSI2); however, whether MSI2 regulates MPNST metastasis and what the mechanism is remain unclear. Here, we demonstrated that the protein caveolin-1 (CAV1) directly interacts with MSI2 in human NF1-MPNST cells. Moreover, we discovered that knockdown of MSI2 induces CAV1 protein expression by inhibiting its ubiquitylation level in NF1-MPNSTs. In addition, CAV1 mediates the suppressive function of MSI2 in epithelial-mesenchymal transition, migration and invasion in vitro and metastasis in vivo. These results help to reveal the potential mechanisms of MSI2 as a target of antimetastatic treatment for human NF1-MPNST.

Context Silver-Russell syndrome (SRS) is a clinical and molecular heterogeneous disorder associated with short stature, typical facial gestalt, and body asymmetry. Though molecular causes of SRS can be identified in a significant number of patients, about one-half of patients currently remain without a molecular diagnosis. However, determination of the molecular cause is required for a targeted treatment and genetic counselling. Objective The aim of this study was to corroborate the role of HMGA2 as an SRS-causing gene and reevaluate its mode of inheritance. Design, Setting, Patients Patients were part of an ongoing study aiming on SRS-causing genes. They were classified according to the Netchine-Harbison clinical scoring system, and DNA samples were investigated by whole exome sequencing. Common molecular causes of SRS were excluded before. Results Three novel pathogenic HMGA2 variants were identified in 5 patients from 3 SRS families, and fulfilling diagnostic criteria of SRS. For the first time, homozygosity for a variant in HMGA2 could be identified in a severely affected sibpair, whereas parents carrying heterozygous variants had a mild phenotype. Treatment with recombinant growth hormone led to a catch-up growth in 1 patient, whereas all others did not receive growth hormone and stayed small. One patient developed type 2 diabetes at age 30 years. Conclusions Identification of novel pathogenic variants confirms HMGA2 as an SRS-causing gene; thus, HMGA2 testing should be implemented in molecular SRS diagnostic workup. Furthermore, inheritance of HMGA2 is variable depending on the severity of the variant and its consequence for protein function.

Background: High mobility group A proteins are involved in chromatin remodeling, thereby influencing multiple fundamental biological processes. HMGA2 has been linked to oncogenic traits among a variety of malignancies. Objective: To determine the prognostic implications of subcellular distribution patterns of HMGA2 in breast cancer. Methods: Nuclear and cytoplasmic HMGA2 was evaluated in 342 breast cancer specimens and matched with clinico-pathological parameters. Results: Overall and cytoplasmic, but not nuclear, levels of HMGA2 correlated with better survival prognoses in our collective (hazard ratio (HR) 0.34, P = 0.001 and HR 0.34, P < 0.001, respectively). The protective effect of cytoplasmic HMGA2 persisted in the Luminal A and triple negative breast cancer subgroups. Evaluating Luminal A and B subgroups jointly, only cytoplasmic, but not overall or nuclear HMGA2 levels were associated with better survival (HR 0.42, 95% confidence interval 0.21, 0.86, P = 0.017), irrespective of tumor size and node status. The addition of HMGA2 overall and cytoplasmic scores strengthened the prognostic selectivity in a model of conventional breast cancer risk factors. No predictive significance with regard to endocrine or chemoendocrine therapies was observed. Conclusion: Unexpectedly, we found a favorable survival probability upon overall levels of HMGA2 in our breast cancer collective, which was predominantly determined by the presence of HMGA2 in the cytoplasm.

Background Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. There are two subtypes, fusion gene-positive RMS (FP-RMS) and fusion gene-negative RMS (FN-RMS), depending on the presence of a fusion gene, either PAX3-FOXO1 or PAX7-FOXO1. These fusion genes are thought to be oncogenic drivers of FP-RMS. By contrast, the underlying mechanism of FN-RMS has not been thoroughly investigated. It has recently been shown that HMGA2 is specifically positive in pathological tissue from FN-RMS, but the role of HMGA2 in FN-RMS remains to be clarified. Methods In this study, we used FN-RMS cell lines to investigate the function of HMGA2. Gene expression, cell growth, cell cycle, myogenic differentiation, tumor formation in vivo, and cell viability under drug treatment were assessed. Results We found that HMGA2 was highly expressed in FN-RMS cells compared with FP-RMS cells and that knockdown of HMGA2 in FN-RMS cells inhibited cell growth and induced G1 phase accumulation in the cell cycle and myogenic differentiation. Additionally, we showed using both gain-of-function and loss-of-function assays that HMGA2 was required for tumor formation in vivo. Consistent with these findings, the HMGA2 inhibitor netropsin inhibited the cell growth of FN-RMS. Conclusions Our results suggest that HMGA2 has important role in the oncogenicity of FP-RMS and may be a potential therapeutic target in patients with FN-RMS.

Pancreatic cancer is one of the most lethal human malignancies, partly because of its propensity for metastasis. However, the mechanisms of metastasis in pancreatic cancer remain unclear. Oxidized low-density lipoprotein receptor 1 (OLR1), a lectin-like scavenger receptor that recognizes several ligands, such as oxidized low-density lipoprotein, was previously reported in cardiovascular and metabolic diseases. The role and mechanism of OLR1 in pancreatic cancer is unclear. In this study, we found that OLR1 expression was significantly higher in pancreatic cancer tissues than that in adjacent normal tissues and closely associated with reduced overall survival. OLR1 promoted proliferation and metastasis of pancreatic cancer cells in vitro and in vivo. Mechanistically, OLR1 increased HMGA2 transcription by upregulating c-Myc expression to promote the metastasis of pancreatic cancer cells. In addition, patients with pancreatic cancer with high expression of OLR1–c-Myc–HMGA2 axis showed worse prognosis compared with patients with low expression of OLR1–c-Myc–HMGA2 axis. Implications: Our findings suggested that the OLR1–c-Myc–HMGA2 axis promotes metastasis of pancreatic cancer cells and may serve as potential therapeutic targets and prognosis markers for patients with pancreatic cancer.

Background The unique geographical environment at high altitudes may cause a series of diseases, such as acute altitude reaction, cerebral edema, and pulmonary edema. Gymnadenia conopsea (L.) R. Br. has been reported to have an effect on high-altitude hypoxia. However, the molecular mechanism, especially the expression of long noncoding RNAs (lncRNAs), is not yet clear. Methods The expression profiles of lncRNAs in high-altitude hypoxia-induced brain injury mice treated with Gymnadenia conopsea (L.) R. Br. by using a microarray method. Results A total of 226 differentially expressed lncRNAs, 126 significantly dysregulated mRNAs and 23 differentially expressed circRNAs were detected (>2.0-fold, p

Protein phosphatase 4 regulatory subunit 1 (PP4R1) has been shown to play a role in the regulation of centrosome maturation, apoptosis, DNA repair, and tumor necrosis factor signaling. However, the function of PP4R1 in non-small-cell lung cancer remains unclear. In this study, we identify PP4R1 as an oncogene through Oncomine database mining and immunohistochemical staining, and we showed that PP4R1 is upregulated in lung cancer tissues as compared with that in normal lung tissues and correlated with a poor prognosis in lung cancer patients. Furthermore, in vitro study by wound-healing and Transwell assay showed that PP4R1 could promote migration and invasion of lung cancer cells. Mechanistic investigations revealed that PP4R1 could cooperate with high mobility group AT-hook 2 and thereby promotes epithelial-mesenchymal transition via MAPK/extracellular receptor kinase activation. Taken together, our study provides a rich resource for understanding PP4R1 in lung cancer and indicates that PP4R1 may serve as a potential biomarker in lung cancer therapies.

Circular RNA (circRNA), as a kind of novel identified non-coding RNA, has become the focus of attention for its vital physiological and pathological roles. However, the function and mechanism of circRNAs in the regulation of cancer progression are largely unknown. In the present study we found a circRNA termed circHMCU whose expression was associated with poor prognosis. It was upregulated in cell lines with high metastatic potential compared with its parental cell line and in breast cancer tissues compared with normal tissues. In vitro results proved that circHMCU could significantly promote proliferation, migration, and invasion abilities of breast cancer cells via affecting the G1 phase cell cycle checkpoint and the epithelial-mesenchymal transition (EMT) pathway. Further in vivo studies showed that overexpression of circHMCU contributed to rapid proliferation and lung metastasis of breast cancer. For determination of the mechanisms, bioinformatics analysis revealed two complementary sequences within circHMCU for let-7 microRNAs, which was validated by a luciferase reporter assay. Finally, let-7 microRNAs could rescue the functions of circHMCU in breast cancer via suppressing the expression of MCY, HMGA2, and CCND1. Taken together, our findings demonstrated that circHMCU exerted oncogenic functions in breast cancer and could be a used as a novel biomarker in the diagnosis and prognosis of breast cancer., Graphical Abstract, circHMCU promotes proliferation and metastasis of breast cancer by sponging the let-7 family and suppressing the expression of MCY, HMGA2, and CCND1, which could be a used as a novel biomarker in the diagnosis and prognosis of breast cancer.