Genome-wide functional integration identified MAZ-controlled RPS14 dysregulation in hepatocellular carcinoma.

Chronic infection with Hepatitis B virus (HBV) significantly increases the risk of hepatocellular carcinoma (HCC), particularly in Eastern Asia. However, only a subset of individuals with chronic HBV infection develop HCC, suggesting the role for genetic factors in HCC etiology. Despite genome-wide association studies (GWASs) identifying multiple single nucleotide polymorphisms (SNPs) associated with HBV-related HCC susceptibility, the underlying mechanisms and causal genetic polymorphisms remain largely unclear. To address this, we developed The Updated Integrative Functional Genomics Approach (TUIFGA), an methodology that combines data from transcription factor (TF) cistromics, ATAC-seq, DNAase-seq, and the 1000 Genomes Project to identify cancer susceptibility SNPs within TF-binding sites across human genome. Using TUIFGA, we discovered SNP rs13170300 which located in the TF MAZ binding motif of RPS14. The RPS14 rs13170300 was significantly associated with HCC risk in two case-control sets, with the T allele as the protective allele (Shandong discovery set: TT OR = 0.60, 95% CI = 0.49-0.74, P = 1.0 × 10-6; CT OR = 0.69, 95% CI = 0.55-0.86, P = 0.001; Jiangsu validation set: TT OR = 0.70, 95% CI = 0.56-0.87, P = 0.001; CT OR = 0.65, 95% CI = 0.53-0.82, P = 1.6 × 10-4). SNP rs13170300 affected MAZ binding in the RPS14 promoter, resulting in allele-specific changes in gene expression. RPS14 functions as a novel oncogene in HCC, specifically via activating the AKT signaling. Our findings present important insights into the functional genetics underlying HBV-related HCC development and may contribute to personalized approaches for cancer prevention and novel therapeutics.

LncPSCA in the 8q24.3 risk locus drives gastric cancer through destabilizing DDX5.

Genome-wide association studies (GWAS) have identified multiple gastric cancer risk loci and several protein-coding susceptibility genes. However, the role of long-noncoding RNAs (lncRNAs) transcribed from these risk loci in gastric cancer development and progression remains to be explored. Here, we functionally characterize a lncRNA, lncPSCA, as a novel tumor suppressor whose expression is fine-regulated by a gastric cancer risk-associated genetic variant. The rs2978980 T > G change in an intronic enhancer of lncPSCA interrupts binding of transcription factor RORA, which down-regulates lncPSCA expression in an allele-specific manner. LncPSCA interacts with DDX5 and promotes DDX5 degradation through ubiquitination. Increased expression of lncPSCA results in low levels of DDX5, less RNA polymerase II (Pol II) binding with DDX5 in the nucleus, thus activating transcription of multiple p53 signaling genes by Pol II. These findings highlight the importance of functionally annotating lncRNAs in GWAS risk loci and the great potential of modulating lncRNAs as innovative cancer therapy.

LncRNA H19 modulated by miR-146b-3p/miR-1539-mediated allelic regulation in transarterial chemoembolization of hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is an effective treatment for unresectable hepatocellular carcinoma (HCC) patients. Although overall survival (OS) of TACE-treated patients has been evidently prolonged, not all unresectable HCC patients can benefit from TACE. Genome-wide association studies identified multiple HCC susceptibility single nucleotide polymorphisms (SNPs). However, it is still unclear how lncRNAs and their functional SNPs impact therapeutic responses of TACE. In the study, we hypothesized that the functional lncRNA H19 SNP(s) might impact H19 expression and, thus, prognosis of TACE-treated HCC patients. We found that the H19 rs3741219 SNP was significantly associated with OS of HCC patients received TACE. Cox proportional hazards model demonstrated that the rs3741219 CC genotype was associated with longer OS and a 37% decreased death risk compared with the TT carriers after TACE therapy (P = 0.001). Interestingly, the rs3741219 T-to-C change led to allelic down-regulation of lncRNA H19 expression via creating the binding sites of miR-146b-3p and miR-1539. Luciferase reporter gene assays indicated that miR-146b-3p and miR-1539 could markedly silence the rs3741219 C-allelic H19 expression but not lncRNA H19 with the T allele. Consistently, there was significantly reduced expression of lncRNA H19 in HCC and normal tissues of the C allele carriers compared with the H19 levels in patients with the T allele. Knock-down of lncRNA H19 significantly promoted the anti-viability efficiency of oxaliplatin (the main chemotherapy drug used in TACE) to HCC cells. In view of these results, we assume that lncRNA H19 might be a potential therapeutic target for unresectable HCC patients.

N6-methyladenosine reader YTHDC2 and eraser FTO may determine hepatocellular carcinoma prognoses after transarterial chemoembolization.

Transarterial chemoembolization (TACE) has significantly improved overall survival (OS) of unresectable hepatocellular carcinoma (HCC) patients. Unfortunately, a portion of patients show no therapeutic responses to TACE. N6-methyladenosine (m6A) as well as its epigenetic writers, erasers, and readers play a crucial role in HCC development. However, it is still largely unclear how functional small nucleotide polymorphisms (SNPs) in m6A-regulating genes contribute to prognosis of TACE-treated HCC patients. In this study, potential functional SNPs were systematically evaluated to identify their roles in the prognosis of HCC patients after TACE in a Chinese Han population. Employing multiple databases, we successfully annotated 55 candidate SNPs. After genotyping these SNPs in our TACE cohort, we identified three genetic variants in YTHDC2 (rs6594732, rs10071816, and rs2303718) and one SNP in FTO (rs7202116) having statistically significant associations with the OS of HCC patients treated with TACE. For example, multivariate Cox proportional hazards model indicated that the rs7202116 GG genotype carriers had markedly shorter OS and an 87% increased death risk compared with the AA carriers after TACE therapy (P = 0.002). When investigating functional relevance of these SNPs, we observed an allelic regulation of rs7202116 on FTO expression in HCC tissue samples, with higher tumor suppressor FTO expression among the A allele carriers. Our findings reported the first evidence supporting the prognostic value of m6A reader YTHDC2 and m6A eraser FTO SNPs in TACE-treated HCC patients. Importantly, our data implicated that m6A-regulating genes may be targets to improve therapeutic strategy for unresectable HCC patients.

Genetic risk, incident gastric cancer, and healthy lifestyle: a meta-analysis of genome-wide association studies and prospective cohort study.

BACKGROUND: Genetic variants and lifestyle factors have been associated with gastric cancer risk, but the extent to which an increased genetic risk can be offset by a healthy lifestyle remains unknown. We aimed to establish a genetic risk model for gastric cancer and assess the benefits of adhering to a healthy lifestyle in individuals with a high genetic risk. METHODS: In this meta-analysis and prospective cohort study, we first did a fixed-effects meta-analysis of the association between genetic variants and gastric cancer in six independent genome-wide association studies (GWAS) with a case-control study design. These GWAS comprised 21 168 Han Chinese individuals, of whom 10 254 had gastric cancer and 10 914 geographically matched controls did not. Using summary statistics from the meta-analysis, we constructed five polygenic risk scores in a range of thresholds (p=5 × 10-4 p=5 × 10-5 p=5 × 10-6 p=5 × 10-7, and p=5 × 10-8) for gastric cancer. We then applied these scores to an independent, prospective, nationwide cohort of 100 220 individuals from the China Kadoorie Biobank (CKB), with more than 10 years of follow-up. The relative and absolute risk of incident gastric cancer associated with healthy lifestyle factors (defined as not smoking, never consuming alcohol, the low consumption of preserved foods, and the frequent intake of fresh fruits and vegetables), was assessed and stratified by genetic risk (low [quintile 1 of the polygenic risk score], intermediate [quintile 2-4 of the polygenic risk score], and high [quintile 5 of the polygenic risk score]). Individuals with a favourable lifestyle were considered as those who adopted all four healthy lifestyle factors, those with an intermediate lifestyle adopted two or three factors, and those with an unfavourable lifestyle adopted none or one factor. FINDINGS: The polygenic risk score derived from 112 single-nucleotide polymorphisms (p<5 × 10-5) showed the strongest association with gastric cancer risk (p=7·56 × 10-10). When this polygenic risk score was applied to the CKB cohort, we found that there was a significant increase in the relative risk of incident gastric cancer across the quintiles of the polygenic risk score (ptrend<0·0001). Compared with individuals who had a low genetic risk, those with an intermediate genetic risk (hazard ratio [HR] 1·54 [95% CI 1·22-1·94], p=2·67 × 10-4) and a high genetic risk (2·08 [1·61-2·69], p<0·0001) had a greater risk of gastric cancer. A similar increase in the relative risk of incident gastric cancer was observed across the lifestyle categories (ptrend<0·0001), with a higher risk of gastric cancer in those with an unfavourable lifestyle than those with a favourable lifestyle (2·03 [1·46-2·83], p<0·0001). Participants with a high genetic risk and a favourable lifestyle had a lower risk of gastric cancer than those with a high genetic risk and an unfavourable lifestyle (0·53 [0·29-0·99], p=0·048), with an absolute risk reduction of 1·12% (95% CI 0·62-1·56). INTERPRETATION: Chinese individuals at an increased risk of incident gastric cancer could be identified by use of our newly developed polygenic risk score. Compared with individuals at a high genetic risk who adopt an unhealthy lifestyle, those who adopt a healthy lifestyle could substantially reduce their risk of incident gastric cancer. FUNDING: National Key R&D Program of China, National Natural Science Foundation of China, 333 High-Level Talents Cultivation Project of Jiangsu Province, and China Postdoctoral Science Foundation.

Oncogene HSPH1 modulated by the rs2280059 genetic variant diminishes EGFR-TKIs efficiency in advanced lung adenocarcinoma.

Although epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy is effective for most advanced non-small-cell lung cancer (NSCLC) patients with mutant EGFR, some patients show little or no response. Germline variations, such as single-nucleotide polymorphisms (SNPs), have been proved to be involved in disease progression after EGFR-TKI therapy. In this study, we hypothesized that the functional HSPH1 SNP may affect gene expression and, thus, prognosis of NSCLC patients treated with EGFR-TKIs. We systematically examined impacts of HSPH1 SNPs on NSCLC survival in two independent cohorts consisted of 319 EGFR-TKI treated stage IIIB/IV NSCLC patients. The promoter rs2280059 polymorphism was significantly associated with patient survival in both cohorts. In vitro and In vivo assays elucidated that rs2280059 G allele shows higher capability to drive HSPH1 promoter activities. Silencing HSPH1 significantly increases the antineoplastic effects of gefitinib on NSCLC cells. Our findings demonstrated potential implications of HSPH1 in clinic, which may lead to better understanding and outcome assessment of EGFR-TKI treatment.

Noncoding RNAs in gastric cancer: implications for drug resistance.

Gastric cancer is the fourth most common malignancy and the third leading cause of cancer-related deaths worldwide. Advanced gastric cancer patients can notably benefit from chemotherapy including adriamycin, platinum drugs, 5-fluorouracil, vincristine, and paclitaxel as well as targeted therapy drugs. Nevertheless, primary drug resistance or acquisition drug resistance eventually lead to treatment failure and poor outcomes of the gastric cancer patients. The detailed mechanisms involved in gastric cancer drug resistance have been revealed. Interestingly, different noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), are critically involved in gastric cancer development. Multiple lines of evidences demonstrated that ncRNAs play a vital role in gastric cancer resistance to chemotherapy reagents and targeted therapy drugs. In this review, we systematically summarized the emerging role and detailed molecular mechanisms of ncRNAs impact drug resistance of gastric cancer. Additionally, we propose the potential clinical implications of ncRNAs as novel therapeutic targets and prognostic biomarkers for gastric cancer.

Silencing of lncRNA PVT1 by miR-214 inhibits the oncogenic GDF15 signaling and suppresses hepatocarcinogenesis.

The prognosis for hepatocellular carcinoma (HCC) is dismal. Long noncoding RNA PVT1 has been linked to malignancies and might be a deleterious therapy target. However, the key events controlling its expression in HCC remain undetermined. Here, we address how PVT1 is fine-regulated and its downstream signaling in hepatoma cells. Interestingly, we found that c-Myc and P53 could divergently regulate PVT1 transcription. Oncoprotein c-Myc enhances PVT1 expression, whereas P53 suppresses its expression. We also identified miR-214 as a crucial, negative regulator of PVT1. Consistently, high miR-214 levels were significantly correlated with diminished PVT1 expression in HCC specimens. Silencing of PVT1 by ectopic miR-214 or siRNAs markedly inhibited viability and invasion of HCC cells. In opposition, inhibition of endogenous miR-214 promoted PVT1 expression and enhanced cell proliferation. Notably, oncogenic GDF15 is a potential downstream target of the miR-214-PVT1 signaling. Collectively, our results show that the c-Myc/P53/miR-214-PVT1-GDF15 axis is implicated in HCC development, shedding light on the mechanistic actions of PVT1 and representing potential targets for HCC clinical intervention.

The long noncoding RNA GAS8-AS1 suppresses hepatocarcinogenesis by epigenetically activating the tumor suppressor GAS8.

Long noncoding RNAs (lncRNAs) are vital players in cancers, including hepatocellular carcinoma (HCC). We previously identified an lncRNA, GAS8-AS1, that is located in intron 2 of GAS8 However, its involvement in HCC is still largely unknown. In this study, we report that both GAS8-AS1 and its host gene GAS8 act as HCC tumor suppressors. We found that expression of GAS8-AS1 or GAS8 is significantly decreased in HCC tissues and is associated with a poor prognosis among HCC patients. Interestingly, lncRNA GAS8-AS1 could promote GAS8 transcription. We detected a CpG island in the GAS8 promoter, but lncRNA GAS8-AS1 did not affect DNA methylation at this GAS8 promoter site. Moreover, we identified two GAS8-AS1-interacting proteins, mixed-lineage leukemia 1 (MLL1), a histone 3 Lys-4 (H3K4) methyltransferase, and its partner WD-40 repeat protein 5 (WDR5). RNA pulldown, ChIP, and RNA immunoprecipitation assays revealed that GAS8-AS1 is required for maintaining the GAS8 promoter in an open chromatin state by recruiting the MLL1/WDR5 complex and for enhancing RNA polymerase II activity and GAS8 transcription. Of note, GAS8-AS1-dependent GAS8 hyperactivation inhibited malignant transformation of hepatocytes. Our results provide important insights into how lncRNA GAS8-AS1 suppresses HCC development and suggest potential strategies for treating patients with liver cancer.

miR-608 and miR-4513 significantly contribute to the prognosis of lung adenocarcinoma treated with EGFR-TKIs.

Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptors (EGFR) significantly prolong the survival of lung adenocarcinoma patients with sensitizing EGFR mutations. Unfortunately, 10-30% patients do not show objective responses to EGFR-TKIs, and undergo rapid disease progression during the EGFR-TKIs therapy. Single nucleotide polymorphisms (SNPs) in mature microRNA (miRNA) sequences may influence target site interactions and modulate downstream pathways, such as the EGFR pathway. For this reason, we hypothesized that miRNA SNPs may impact the prognosis of lung adenocarcinoma patients after EGFR-TKI treatment. By systematically screening of the miRbase and the 1000 genomes project databases, we successfully identified five mature miRNA SNPs. Genotypes were determined in two independent cohorts (Hubei and Shandong cohorts) that include 319 EGFR-TKI treated stage IIIB/IV patients. The impact of miR-608 and miR-4513 on the drug sensitivity of gefitinib was examined in lung adenocarcinoma cells. miR-608 rs4919510 or miR-4513 rs2168518 significantly contributed to the progression-free survival (PFS) in the Hubei cohort (hazard ratio [HR] = 0.63, confidence interval [CI] = 0.49-0.81, P = 3.0 × 10-4 or HR = 0.46, 95% CI = 0.31-0.67, P = 8.0 × 10-5). These observations were further validated in the Shandong cohort (P = 0.005 or P = 0.001). Similarly, the miR-608 rs4919510 CC genotype or the miR-4513 rs2168518 GA genotype was significantly associated with decreased death risk after gefitinib treatment, compared with the rs4919510 GG genotype (Hubei cohort: P = 5.0 × 10-4; Shandong cohort: P = 0.004) or the rs2168518 GG genotype (P = 4.9 × 10-5; P = 0.002). Consistently, miR-608 significantly increased the anti-proliferation effect of gefitinib in both lung adenocarcinoma PC9 and H1299 cells, whereas miR-4513 increased cells' resistance to gefitinib. Our findings suggest that miR-608 and miR-4513 SNPs are independent candidate biomarkers to predict lung adenocarcinoma patients' survival after EGFR-TKIs treatment. These miRNAs and polymorphisms provide clinical potential in patient-tailored treatment decision-making.

The emerging role of microRNAs and long noncoding RNAs in drug resistance of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the second most lethal human cancer. A portion of patients with advanced HCC can significantly benefit from treatments with sorafenib, adriamycin, 5-fluorouracil and platinum drugs. However, most HCC patients eventually develop drug resistance, resulting in a poor prognosis. The mechanisms involved in HCC drug resistance are complex and inconclusive. Human transcripts without protein-coding potential are known as noncoding RNAs (ncRNAs), including microRNAs (miRNAs), small nucleolar RNAs (snoRNAs), long noncoding RNAs (lncRNAs) and circular RNA (circRNA). Accumulated evidences demonstrate that several deregulated miRNAs and lncRNAs are important regulators in the development of HCC drug resistance which elucidates their potential clinical implications. In this review, we summarized the detailed mechanisms by which miRNAs and lncRNAs affect HCC drug resistance. Multiple tumor-specific miRNAs and lncRNAs may serve as novel therapeutic targets and prognostic biomarkers for HCC.

Genetic variations associated with telomere length confer risk of gastric cardia adenocarcinoma.

BACKGROUND: Aberrant telomere lengthening is a critical feature of malignant cells. Short leukocyte telomere length (LTL) confers elevated risk of gastric cardia adenocarcinoma (GCA). Multiple genome-wide association studies (GWAS) identified various single-nucleotide polymorphisms (SNPs) associated with LTL in different ethnic populations. However, it remains largely unexplored how these genetic variants are involved in GCA susceptibility. METHODS: We systematically screened GWAS-identified candidate SNPs and tested the impact of 30 polymorphisms in genes associated with interindividual LTL variation on GCA using two-stage case-control comparisons consisting of 1024 GCA patients and 1118 controls. RESULTS: We observed that CXCR4 rs6430612, TERT rs10069690, and rs2853676 as well as VPS34 rs2162440 are significantly associated with GCA development. A 0.64-fold decreased risk of GCA is associated with the CXCR4 rs6430612 CT genotype compared with the CC genotype (P = 0.002). On the contrary, the TERT rs10069690 TT genotype carriers had a 1.83-fold increased risk to develop GCA compared to the CC genotype carriers (P = 5.8×10-6). We also detected a 2.17-fold increased OR for GCA that was associated with the TERT rs2853676 TT genotype (P = 2.6×10-6). In addition, the odds of having the VPS34 rs2162440 GA genotype in GCA patients were 1.35 compared with the GG genotype (P = 0.002). In stratified analyses, the association between TERT rs10069690 polymorphism and GCA was more pronounced in nonsmokers (Pinteraction = 9.7 × 10-5) and nondrinkers (Pinteraction = 4.6 × 10-5). CONCLUSIONS: Our results highlight the importance of both LTL and LTL-related genetic variants to GCA predisposition.

LncRNA CDKN2BAS rs2157719 genetic variant contributes to medulloblastoma predisposition.

BACKGROUND: How germline single nucleotide polymorphisms are involved in the etiology of medulloblastoma remans poorly understood. We hypothesized that CCDKN2A/B rs1063192 and rs4977756 and also the long noncoding RNA (lncRNA) CDKN2BAS rs2157719 glioma susceptibility polymorphisms identified by genome-wide association studies may contribute to medulloblastoma predisposition. METHODS: To test this hypothesis, we genotyped these genetic variants among 160 medulloblastoma patients and 443 health controls in a Chinese population. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. RESULTS: We found that only the lncRNA CDKN2BAS rs2157719 T>C genetic polymorphism was significantly associated with an increased medulloblastoma risk (C allele: OR = 1.85, 95% CI = 1.32-2.58; p = 2.7 × 10-4 ). The stratified analyses showed an elevated risk of pediatric medulloblastoma associated with CDKN2BAS rs2157719 CC or TC genotype (both p < 0.05). Moreover, the association between the CDKN2BAS rs2157719 polymorphism and medulloblastoma risk is more pronounced in males (OR = 2.22, 95% CI = 1.36-3.62; p = 0.001). CONCLUSIONS: The findings of the present study provide important insights into the genetic complexities and predisposition of medulloblastoma in Chinese, especially at the lncRNA germline variation level.

The TDP-43/TP63 Positive Feedback Circuit Promotes Esophageal Squamous Cell Carcinoma Progression.

Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent malignancies with a 5-year survival rate of only 15% in patients with advanced diseases. Tumor protein 63 (TP63), a master transcription factor (TF) in ESCC, cooperates with other TFs to regulate enhancers and/or promoters of target oncogenes, which in turn promotes tumorigenesis. TAR-DNA-binding protein-43 (TDP-43) is an RNA/DNA binding protein with elevated expression in several neoplasms. However, it remains unclear how TDP-43 contributes to ESCC progression. In this study, TDP-43 is identified as a novel oncogene with markedly upregulated expression in ESCC tissues through profiling expression levels of one hundred and fifty canonical RNA binding protein (RBP) genes in multiple ESCC patient cohorts. Importantly, TDP-43 boosted TP63 expression via post-transcriptionally stabilizing TP63 mRNAs as a RBP and promoting TP63 transcription as a TF binding to the TP63 promoter in ESCC cells. In contrast, the master TF TP63 also bound to the TDP-43 promoter, accelerated TDP-43 transcription, and caused a noticeable increase in TDP-43 expression in ESCC cells. The findings highlight TDP-43 as a viable therapeutic target for ESCC and uncover a hitherto unrecognized TDP-43/TP63 circuit in cancer.

Super-enhancers: Implications in gastric cancer.

Gastric cancer (GC) is the fifth most prevalent malignancy and the third leading cause of cancer-related mortality globally. Despite intensive efforts to enhance the efficiencies of various therapeutics (chemotherapy, surgical interventions, molecular-targeted therapies, immunotherapies), the prognosis for patients with GC remains poor. This might be predominantly due to the limited understanding of the complicated etiology of GC. Importantly, epigenetic modifications and alterations are crucial during GC development. Super-enhancers (SEs) are a large cluster of adjacent enhancers that greatly activate transcription. SEs sustain cell-specific identity by enhancing the transcription of specific oncogenes. In this review, we systematically summarize how SEs are involved in GC development, including the SE landscape in GC, the SE target genes in GC, and the interventions related to SE functions for treating GC.

Long non-coding RNAs in non-small cell lung cancer: implications for preventing therapeutic resistance.

Lung cancer has the highest mortality and morbidity rates among all cancers worldwide. Despite many complex treatment options, including radiotherapy, chemotherapy, targeted drugs, immunotherapy, and combinations of these treatments, efficacy is low in cases of resistance to therapy, metastasis, and advanced disease, contributing to low overall survival. There is a pressing need for the discovery of novel biomarkers and therapeutic targets for the early diagnosis of lung cancer and to determine the efficacy and outcomes of drug treatments. There is now substantial evidence for the diagnostic and prognostic value of long noncoding RNAs (lncRNAs). This review briefly discusses recent findings on the roles and mechanisms of action of lncRNAs in the responses to therapy in non-small cell lung cancer.

New insights on the interplays between m6A modifications and microRNA or lncRNA in gastrointestinal cancers.

N6-Methyladenosine (m6A) methylation is one of the most extremely examined RNA modifications. M6A modification evidently impacts cancer development by effecting RNA metabolism. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are involved in multiple essential biological processes by regulating gene expression at the transcriptional and post-transcriptional levels. Accumulated evidences indicated that m6A is involved in regulating the cleavage, stability, structure, transcription, and transport of lncRNAs or miRNAs. Additionally, ncRNAs also play significant roles in modulating m6A levels of malignant cells by participating in the regulation of m6A methyltransferases, the m6A demethylases and the m6A binding proteins. In this review, we systematically summarize the new insight on the interactions between m6A and lncRNAs or miRNAs, as well as their impacts on gastrointestinal cancer progression. Although there are still extensive studies on genome-wide screening of crucial lncRNAs or miRNAs involved in regulating m6A levels of mRNAs and disclosing differences on mechanisms of regulating m6A modification of lncRNAs, miRNAs or mRNAs in cancer cells, we believe that targeting m6A-related lncRNAs and miRNAs may provide novel options for gastrointestinal cancer treatments.

CircPDIA4 Induces Gastric Cancer Progression by Promoting ERK1/2 Activation and Enhancing Biogenesis of Oncogenic circRNAs.

Circular RNAs (circRNA) are a group of noncoding, covalently uninterrupted loop transcripts, most of which remain to be functionally characterized. Here, we identified circPDIA4 as an oncogenic circRNA in gastric cancer. Clinically, circPDIA4 was significantly upregulated in malignant tissues and was associated with poor survival of patients with gastric cancer. The biogenesis of circPDIA4 was mediated by the RNA-binding protein Quaking, which bound introns 2 and 4 of PDIA4 pre-mRNA to promote backsplicing of exons 3 and 4. Elevated expression of circPDIA4 promoted distant metastasis in various mouse xenograft models in vivo and accelerated cancer cell invasion in vitro. CircPDIA4 functioned through distinct oncogenic mechanisms in the cytoplasm and the nucleus. Cytoplasmic circPDIA4 bound to ERK1/2 and sustained hyperactivation of the MAPK pathway by preventing DUSP6-mediated ERK1/2 dephosphorylation. Notably, circPDIA4 depletion enhanced the sensitivity of gastric cancer cells to ERK inhibitors. In the nucleus, circPDIA4 interacted with DHX9 as a decoy and repressed its inhibitory functions on circRNA biogenesis to boost expression of multiple oncogenic circRNAs, which promoted gastric cancer progression. These findings reveal a dual tumor-promoting mechanism for circPDIA4 by regulating oncogenic circRNA biogenesis and increasing MAPK activity. CircPDIA4 should be investigated further as a potential prognostic biomarker and therapeutic target in gastric cancer. SIGNIFICANCE: Quaking-regulated circPDIA4 mediates different mechanisms in the nucleus and cytoplasm that coordinate to promote progression and drug resistance in gastric cancer.

The allelic regulation of tumor suppressor ADARB2 in papillary thyroid carcinoma.

Papillary thyroid cancer (PTC) is one of the histological subtypes of thyroid cancer which is the most common endocrine malignancy in the world. The disrupted balance of the adenosine-to-inosine (A-to-I) RNA editing due to dysregulation of the editing genes exists in thyroid cancer. However, it is still largely unknown how functional single-nucleotide polymorphisms (SNPs) in the A-to-I RNA editing genes contribute to PTC genetic susceptibility. In this study, we systematically annotated and investigated the role of 28 potential functional SNPs of ADAR, ADARB1, ADARB2 and AIMP2 in PTC. We identified ADARB2 rs904957 and rs1007147 genetic variants which are associated with significantly elevated PTC risk in two case-control sets consisting of 2020 PTC cases and 2021 controls. Further investigations disclosed that ADARB2 could inhibit cell viability and invasion capabilities of PTC cells as a novel tumor suppressor. The ADARB2 rs904957 thymine-to-cytosine (T-to-C) polymorphism in gene 3'-untranslated region enhances miR-1180-3p-binding affinity and represses ADARB2 expression through an allele-specific manner. In line with this, carriers with the rs904957 C allele correlated with decreased tumor suppressor ADARB2 expression in tissue specimens showed notably increased risk of developing PTC compared to the T allele carriers. Our findings highlight that the A-to-I RNA editing gene ADARB2 SNPs confer PTC risk. Importantly, these insights would improve our understanding for the general roles of RNA editing and editing genes during cancer development.

LINC00240 in the 6p22.1 risk locus promotes gastric cancer progression through USP10-mediated DDX21 stabilization.

BACKGROUND: Gastric cancer remains the leading cause of cancer death in the world. It is increasingly evident that long non-coding RNAs (lncRNAs) transcribed from the genome-wide association studies (GWAS)-identified gastric cancer risk loci act as a key mode of cancer development and disease progression. However, the biological significance of lncRNAs at most cancer risk loci remain poorly understood. METHODS: The biological functions of LINC00240 in gastric cancer were investigated through a series of biochemical assays. Clinical implications of LINC00240 were examined in tissues from gastric cancer patients. RESULTS: In the present study, we identified LINC00240, which is transcribed from the 6p22.1 gastric cancer risk locus, functioning as a novel oncogene. LINC00240 exhibits the noticeably higher expression in gastric cancer specimens compared with normal tissues and its high expression levels are associated with worse survival of patients. Consistently, LINC00240 promotes malignant proliferation, migration and metastasis of gastric cancer cells in vitro and in vivo. Importantly, LINC00240 could interact and stabilize oncoprotein DDX21 via eliminating its ubiquitination by its novel deubiquitinating enzyme USP10, which, thereby, promote gastric cancer progression. CONCLUSIONS: Taken together, our data uncovered a new paradigm on how lncRNAs control protein deubiquitylation via intensifying interactions between the target protein and its deubiquitinase. These findings highlight the potentials of lncRNAs as innovative therapeutic targets and thus lay the ground work for clinical translation.