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Small nucleolar RNA SNORD50A and SNORD50B (SNORD50A/B) has been reported to be recurrently deleted and function as a putative tumor suppressor in different types of cancer by binding to and suppressing the activity of the KRAS oncoproteins. Its deletion correlates with poorer patient survival. However, in this study, we surprisingly found that SNORD50A/B loss predicted a better survival in breast cancer patients carrying wild-type p53. Functional studies showed that SNORD50A/B deletion strongly inhibited the proliferation, migration, invasion and tumorigenic potential, and induced cell cycle arrest and apoptosis in p53 wild-type breast cancer cells, while exerted the opposite effects in p53 mutated breast cancer cells. This was also supported by ectopically expressing SNORD50A/B in both p53 wild-type and mutated breast cancer cells. Mechanistically, SNORD50A/B clearly enhances the interaction between E3 ubiquitin ligase TRIM21 and its substrate GMPS by forming a complex among them, thereby promoting GMPS ubiquitination and its subsequent cytoplasmic sequestration. SNORD50A/B deletion in p53 wild-type breast cancer cells will release GMPS and induce the translocation of GMPS into the nucleus, where GMPS can recruit USP7 and form a complex with p53, thereby decreasing p53 ubiquitination, stabilizing p53 proteins, and inhibiting malignant phenotypes of cancer cells. Altogether, the present study first reports that SNORD50A/B plays an oncogenic role in p53 wild-type breast cancers by mediating TRIM21-GMPS interaction.

Solute carrier family 39 member 10 (SLC39A10) belongs to a subfamily of zinc transporters and plays a key role in B-cell development. Previous studies have reported that its upregulation promotes breast cancer metastasis by enhancing the influx of zinc ions (Zn 2+ ); however, its role in gastric cancer remains totally unclear. Here, we found that SLC39A10 expression was frequently increased in gastric adenocarcinomas and that SLC39A10 upregulation was strongly associated with poor patient outcomes; in addition, we identified SLC39A10 as a direct target of c-Myc. Functional studies showed that ectopic expression of SLC39A10 in gastric cancer cells dramatically enhanced the proliferation, colony formation, invasiveness abilities of these gastric cancer cells and tumorigenic potential in nude mice. Conversely, SLC39A10 knockdown inhibited gastric cancer cell proliferation and colony formation. Mechanistically, SLC39A10 exerted its carcinogenic effects by increasing Zn 2+ availability and subsequently enhancing the enzyme activity of CK2 (casein kinase 2). As a result, the MAPK/ERK and PI3K/AKT pathways, two major downstream effectors of CK2, were activated, while c-Myc, a downstream target of these two pathways, formed a vicious feedback loop with SLC39A10 to drive the malignant progression of gastric cancer. Taken together, our data demonstrate that SLC39A10 is a functional oncogene in gastric cancer and suggest that targeting CK2 is an alternative therapeutic strategy for gastric cancer patients with high SLC39A10 expression. Gastric cancer: Zinc transporter protein fuels disease progression A zinc transporter protein that is upregulated in gastric and other cancers offers a potential treatment target. Zinc is a vital trace element in the body, and a structural and catalytic component of many enzymes. Scientists know that the upregulation of the zinc transporter protein SLC39A10 enhances the influx of zinc ions into breast and liver cancer cells, boosting proliferation and metastasis. However, the role of SLC39A10 in other cancers is unclear. Xiaojuan Ren and co-workers at Xi’an Jiaotong University in Xi’an, China, found that SLC39A10 is upregulated in human gastric cancer cells and this increase is linked to poor prognosis. SLC39A10 increased the invasiveness of gastric cancer cells and their tumorigenic potential in mouse models. The team outlined the mechanisms behind SLC39A10 activity, highlighting two key pathways and identifying a possible treatment route.

Hepatitis B virus (HBV) infection is the primary cause of hepatocellular carcinoma (HCC). Zinc-finger protein 382 (ZNF382), which belongs to zinc-finger protein family, has been documented to be downregulated in certain types of cancer. However, its role in HCC remains largely unknown. In this study, we demonstrated that ZNF382 expression was significantly elevated in HBV-infected liver cirrhosis tissues relative to HBV-negative normal liver tissues at protein levels, but not at mRNA levels, and was positively correlated with the levels of HBV DNA and hepatitis B virus X protein (HBx). Further studies revealed that ZNF382 was a target of miR-6867, and HBx promoted the translation of ZNF382 during HBV chronic infection through Erk-mediated miR-6867 inhibition. In addition, our data showed that ZNF382 was frequently downregulated by promoter methylation in HBV-related HCCs relative to HBV-infected liver cirrhosis tissues, and decreased expression of ZNF382 was strongly correlated with poor survival in early-stage HCC patients. Functional studies demonstrated that ZNF382 was a potent tumor suppressor in HCC cells through inhibiting cell proliferation, colony formation, migration, invasion, and tumorigenic potential in nude mice, and inducing cell apoptosis. Mechanistically, ZNF382 exerted its tumor-suppressor functions in HCC through transcriptionally repressing its downstream targets such as Fos proto-oncogene (FOS), Jun proto-oncogene (JUN), disheveled segment polarity protein 2 (DVL2), and frizzled class receptor 1 (FZD1), thereby impairing the activities of activating protein 1 (AP-1) and Wnt/β-catenin pathways and activating p53 signaling. Altogether, our data show that ZNF382 acts as a tumor suppressor, and is co-regulated by HBx and epigenetic mechanism in HBV-related hepatocellular carcinogenesis.

Hepatocellular carcinoma (HCC) remains one of the most lethal malignancies, with limited efficacy of systemic therapies due to poor survival benefit and drug resistance. Dolichyl-diphosphooligosaccharide-protein glycosyltransferase noncatalytic subunit (DDOST), a critical component of oligosaccharyltransferase (OST), is upregulated in multiple cancers, yet its role in HCC is unclear. Here we demonstrate that DDOST expression is elevated in HCC tissues and correlated with poor prognosis. Functional studies showed that DDOST knockdown suppressed cell proliferation, induced cell cycle arrest and enhanced their lenvatinib sensitivity both in vitro and in vivo. Mechanistically, DDOST depletion impaired EGFR N-glycosylation, suppressing downstream AKT, ERK5 and ERK1/2 signaling, thereby sensitizing HCC cells to lenvatinib. Loss of DDOST also reduced PD-L1 glycosylation. Furthermore, the OST inhibitor NGI-1 and NGI-1-loaded nanoparticles exerted potent antitumor effects and further augmented the efficacy of lenvatinib and immunotherapy. These findings highlight DDOST as a promising therapeutic target to improve treatment outcomes in HCC. DDOST targeting enhances lenvatinib efficacy in HCC Primary liver cancer, particularly hepatocellular carcinoma (HCC), is a major global health issue. Despite advances in treatment, many patients develop resistance to drugs such as lenvatinib, a common therapy. Researchers explored how a protein called DDOST might contribute to this resistance. They studied HCC cells and found that DDOST is often overactive in these cancers, helping the cancer cells survive and resist treatment. By reducing DDOST activity, they observed that cancer cells became more sensitive to lenvatinib. This was because DDOST affects a process called N-glycosylation, which is crucial for the activity of proteins such as EGFR and PD-L1 involved in cancer growth and immune evasion. The study suggests that targeting DDOST could improve the effectiveness of existing treatments for HCC. In the future, therapies that inhibit DDOST might enhance the response to both lenvatinib and immunotherapy. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

In subclinical hypothyroidism, the levels of serum thyroid-stimulating hormone (TSH) are positively correlated with insulin resistance; however, the precise mechanism is unclear. Except for thyroid follicular epithelial cells, macrophages express the highest levels of TSHR . Thus, we speculate that TSH may promote insulin resistance by triggering macrophage inflammation. Here we established a mouse model of TSH receptor ( Tshr ) myeloid-specific knockout ( Tshr MKO ) and found that Tshr MKO mice showed improvement on high-fat diet-induced obesity and insulin resistance compared with wild-type mice ( Tshr f/f ). In addition, Tshr MKO mice exhibited decreased infiltration and M1 polarization of macrophages in liver, adipose and skeletal muscle. Co-culture experiments proved that Tshr -deficient macrophages decreased gluconeogenesis in hepatocytes but increased glucose uptake in adipocytes and skeletal muscle cells by improving the insulin signaling pathway. Mechanistically, increased TSH levels in subclinical hypothyroidism promoted the secretion of cytokines IL-1α, IL-1β and IL-6 by inducing macrophage M1 polarization, which upregulated EGR1 to transcriptionally activate LCN2 and SOCS3 in insulin target cells, thereby exacerbating insulin resistance. These effects could be reversed by IL-1 and IL-6 blockers IL-1RA and IL-6ST. Thus, we provided mechanistic insights into the predisposition to insulin resistance in subclinical hypothyroidism and revealed the role of TSH in metabolic disorders. TSH induces macrophage inflammation linked to insulin resistance Subclinical hypothyroidism is a condition in which the thyroid-stimulating hormone (TSH) levels are high, but thyroid hormone levels are normal, and the levels of serum TSH are positively correlated with insulin resistance. Researchers investigated this by using mice with a specific genetic modification that affects TSH receptors in macrophages. The study found that high TSH levels can cause these macrophages to become more inflammatory, which, in turn, worsens insulin resistance. The researchers used a mouse model to show that, when TSH receptors were removed from macrophages, the mice had better insulin sensitivity and less inflammation. This suggests that TSH plays a role in promoting inflammation and insulin resistance. The findings indicate that managing TSH levels in patients with subclinical hypothyroidism could help to reduce their risk of developing insulin resistance and related conditions such as type 2 diabetes. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Ten eleven translocation 1 (TET1) is a 5-methylcytosine dioxygenase, and its altered DNA demethylation has been implicated in human diseases. However, its role in regulating thyroid function remains totally unknown. Here we first generated thyroid-specific Tet1 knockout combined with thyroid-specific Braf V600E transgenic mouse model ( Thy-Braf V600E ; Tet1 −/− ) and their control mice ( Thy-Braf V600E ; Tet1 +/+ ). The latter developed severe hypothyroidism and lost reproductive ability owing to structural damages of thyroid gland, while thyroid-specific Tet1 knockout effectively restored thyroid structure and function of Thy-Braf V600E ; Tet1 +/+ mice and their reproductive ability. In addition, we also established thyroid-specific Tet1 knockout mouse model ( Thy-Tet1 −/− ) and demonstrated that these mice could develop hyperthyroidism with systemic hypermetabolic symptoms such as weight loss, increased heart rate and elevated systolic blood pressure, further supporting the inhibitory effect of TET1 on thyroid function. Transcriptomic sequencing revealed that key genes related to metabolism and synthesis of thyroid hormones such as PAX8 , SLC5A5 and TPO were significantly upregulated in Thy-Tet1 −/− mice. Mechanistically, TET1 recruits HDAC1 to reduce the levels of H3K27Ac and H3K9Ac in the PAX8 promoter, thereby inhibiting the expression of itself and its downstream targets NIS and TPO. Further studies showed that elevated miR-29c-3p in serum exosomes enhanced thyroid function by targeting TET1, which may be one of the causes of hyperthyroidism. Thus, this study uncovers a new mechanism by which TET1 suppresses thyroid function, providing a new perspective to explore the pathogenesis of hyperthyroidism. TET1 regulates thyroid function and hyperthyroidism mechanisms Hyperthyroidism is a condition in which the thyroid gland produces too many hormones, leading to symptoms such as weight loss and irritability. Here scientists are exploring the role of a protein called TET1 in thyroid function. TET1 is known for its role in modifying DNA, which can affect how genes are turned on or off. In this study, researchers investigated whether TET1 influences thyroid activity. They used mice that were genetically modified to lack TET1 specifically in their thyroid glands. These mice showed signs of hyperthyroidism such as increased thyroid hormone levels and faster metabolism. The researchers found that TET1 normally helps suppress the activity of certain genes involved in thyroid hormone production by interacting with other proteins that modify DNA structure. This study suggests that TET1 plays a crucial role in regulating thyroid function and that its absence can lead to hyperthyroidism. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Accumulating evidence supports evolutionary trait of drug resistance. Like resilience in other systems, most tumor cells experience drug-tolerant state before full resistance acquired. However, the underlying mechanism is still poorly understood. Here, we identify that EGF like domain multiple 7 ( EGFL7 ) is a responsive gene to epidermal growth factor receptor (EGFR) kinase inhibition during a period when tumors are decimated. Moreover, our data reveal that the adaptive increase of EGFL7 during this process is controlled by the depression of nonsense-mediated mRNA decay (NMD) pathway. Upregulation of EGFL7 activates NOTCH signaling in lung cancer cells, which slows down the decrease of c-Myc caused by EGFR inhibition, thereby helping the survival of cancer cells. Our data, taken together, demonstrate that EGFL7 is a driver gene for resistance to EGFR kinase inhibition, and suggest that targeting EGFL7/NOTCH signaling may improve the clinical benefits of EGFR inhibitors in patients with EGFR mutant tumors.

Neurofibromatosis type 1 (NF1), an autosomal dominant and multisystem disorder, is generally considered to be caused by NF1 inactivation. However, there are also numerous studies showing that Neurofibromatosis type 1-like phenotype can be caused by the abnormalities in the other genes. Through targeted parallel sequencing, whole-exome sequencing, de novo genomic sequencing, and RNA isoform sequencing, we identified a germline V2097M variation in CSPG4 gene probably increased susceptibility to a NF1-like phenotype family. Besides, a series of in vitro functional studies revealed that this variant promoted cell proliferation by activating the MAPK/ERK signaling pathway via hindering ectodomain cleavage of CSPG4. Our data demonstrate that a germline variation in the CSPG4 gene might be a high risk to cause NF1-like phenotype. To our knowledge, this is the first report of mutations in the CSPG4 gene in human diseases.

Background MicroRNAs (miRNAs) are a large group of negative gene regulators that potentially play a critical role in tumorigenesis. Increasing evidences indicate that miR-145 acts a tumor suppressor in numerous human cancers. However, its role in oral carcinogenesis remains poorly defined. The aim of this study is to determine expression levels of miR-145 in oral squamous cell carcinomas (OSCCs) and normal mucosa tissues, and explore its biological functions in OSCCs. Methods Reverse transcription quantitative real-time PCR (RT-qPCR) assay was used to evaluate expression levels of miR-145. The biological functions of miR-145 were determined by cell proliferation and colony formation, cell cycle and apoptosis, as well as cell invasion assay. Results MiR-145 was frequently down-regulated in OSCCs compared with normal mucosa tissues. Restoring miR-145 expression in OSCC cells dramatically suppressed cell proliferation and colony formation, and induced G1 phase arrest and cell apoptosis. Importantly, our data showed that miR-145 downregulated the expression of c-Myc and Cdk6, which have previously been identified as two direct targets of miR-145. Conclusions Our data suggest that miR-145 exerts its tumor suppressor function by targeting c-Myc and Cdk6, leading to the inhibition of OSCC cell growth. MiR-145 rescue may thus be a rational for diagnostic and therapeutic applications in OSCC.

Background Lung cancer is the leading cause of cancer-related death worldwide. Genetic and epigenetic alterations have been identified frequently in lung cancer, such as promoter methylation, gene mutations and genomic amplification. However, the interaction between genetic and epigenetic events and their significance in lung tumorigenesis remains poorly understood. Methods We determined the promoter methylation of 6 genes and PIK3CA amplification using quantitative methylation-specific PCR (Q-MSP) and real-time quantitative PCR, respectively, and explore the association of promoter methylation with PIK3CA amplification in a large cohort of clinically well-characterized non-small cell lung cancer (NSCLC). Results Highly frequent promoter methylation was observed in NSCLC. With 100% diagnostic specificity, excellent sensitivity, ranging from 45.8 to 84.1%, was found for each of the 6 genes. The promoter methylation was associated with histologic type. Methylation of CALCA, CDH1, DAPK1 , and EVX2 was more common in squamous cell carcinomas (SCC) compared to adenocarcinomas (ADC). Conversely, there was a trend toward a higher frequency of RASSF1A methylation in ADC than SCC. In addition, PIK3CA amplification was frequently found in NSCLC, and was associated with certain clinicopathologic features, such as smoking history, histologic type and pleural indentation. Importantly, aberrant promoter methylation of certain genes was significantly associated with PIK3CA amplification. Conclusions Our data showed highly frequent promoter methylation and PIK3CA amplification in Chinese NSCLC population, and first demonstrated the associations of gene methylation with PIK3CA amplification, suggesting that these epigenetic events may be a consequence of overactivation of PI3K/Akt pathway.