Progression Of Esophageal Squamous Cell Carcinoma Research Articles

CircGFPT1 regulates the growth and apoptosis of esophageal squamous cell carcinoma through miR-142-5p/HAX1 axis.

Currently, multiple circular RNAs (circRNAs) have been verified to act as essential regulators in the progression of esophageal squamous cell carcinoma (ESCC). However, there is no study regarding the role of circGFPT1 in the progression of cancers including ESCC. We aimed to investigate the role of circGFPT1 in ESCC progression. Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized to measure the expression of circGFPT1, miR-142-5p and HS1-associated protein X-1 (HAX1). 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and 5-ethynyl-2'-deoxyuridine (EdU) assays were employed to evaluate cell proliferation. Cell migration and invasion were detected by wound-healing and transwell assays. Flow cytometry analysis was conducted to assess cell apoptosis. The protein expression of E-cadherin, N-cadherin, Vimentin, C-caspase3, HAX1 and nuclear proliferation marker (Ki67) was analyzed by western blot or immunohistochemistry assay. CircGFPT1 was up-regulated in ESCC tissues and cells. Silencing of circGFPT1 repressed cell proliferation and induced cell apoptosis in ESCC cells. CircGFPT1 acted as a sponge of miR-142-5p. The effects of circGFPT1 knockdown on ESCC cell proliferation and apoptosis were reversed by miR-142-5p inhibition. HAX1 was confirmed to be a target gene of miR-142-5p. CircGFPT1 knockdown inhibited HAX1 expression by targeting miR-142-5p. Additionally, circGFPT1 knockdown hampered tumorigenesis in vivo. CircGFPT1 promoted ESCC cell growth and repressed apoptosis by up-regulating HAX1 through sponging miR-142-5p.

Investigation of Clinical Significant Utility of LncRNA-LINC02389 in Patients with Esophageal Squamous Cell Carcinoma

Background: The lncRNA-LINC02389 gene is a long non-coding RNA, which has not been an assessed potential role in the pathogenesis of esophageal squamous cell carcinoma (ESCC). Objectives: The purpose of the present survey was to evaluate the lncRNA-LINC02389 gene expression variation in subjects with ESCC. Methods: The present survey was a preliminary investigation performed on seventy-five paired paraffin blocks including tumorous and non-tumorous marginal tissues from subjects with ESCC. After extraction of total RNA and cDNA synthesis, the lncRNA-LINC02389 gene expression change was evaluated using quantitative real-time PCR method. Results: Our data declared that the lncRNA-LINC02389 gene was significantly down-regulated in ESCC tissues compared to the marginal tissues (P < 0.05). In addition, the findings showed a significant association between the lncRNA-LINC02389 gene expression change and tumor differentiation grade (P = 0.003). Conclusions: Our results proposed a possible carcinogenesis character of the lncRNA-LINC02389 gene and may be employed as a prognostic clinical significance in the progression of ESCC.

Circular RNA circ-FIRRE interacts with HNRNPC to promote esophageal squamous cell carcinoma progression by stabilizing GLI2 mRNA.

Increasing evidence has shown that circular RNAs (circRNAs) interact with RNA-binding proteins (RBPs) and promote cancer progression. However, the function and mechanism of the circRNA/RBP complex in esophageal squamous cell carcinoma (ESCC) are still largely unknown. Herein, we first characterized a novel oncogenic circRNA, circ-FIRRE, by RNA sequencing (Ribo-free) profiling of ESCC samples. Furthermore, we observed marked circ-FIRRE overexpression in ESCC patients with high TNM stage and poor overall survival. Mechanistic studies indicated that circ-FIRRE, as a platform, interacts with the heterogeneous nuclear ribonucleoprotein C (HNRNPC) protein to stabilize GLI2 mRNA by directly binding to its 3'-UTR in the cytoplasm, thereby resulting in elevated GLI2 protein expression and subsequent transcription of its target genes MYC, CCNE1, and CCNE2, ultimately contributing to ESCC progression. Moreover, HNRNPC overexpression in circ-FIRRE knockdown cells notably abolished circ-FIRRE knockdown-mediated Hedgehog pathway inhibition and ESCC progression impairment in vitro and in vivo. Clinical specimen results showed that circ-FIRRE and HNRNPC expression was positively correlated with GLI2 expression, which reveals the clear significance of the circ-FIRRE/HNRNPC-GLI2 axis in ESCC. In summary, our results indicate that circ-FIRRE could serve as a valuable biomarker and potential therapeutic target for ESCC and highlight a novel mechanism of the circ-FIRRE/HNRNPC complex in ESCC progression regulation.

Hsa-miR-1269a up-regulation fosters the malignant progression of esophageal squamous cell carcinoma via targeting FAM46C

Esophageal squamous cell carcinoma (ESCC) is a malignancy of the alimentary tract resulting in death worldwide. The role and underlying mechanism of hsa-miR-1269a in the progression of ESCC remain unclear. In this study, hsa-miR-1269a was screened by differential expression analysis in TCGA, and its target gene FAM46C was predicted. qRT-PCR was conducted to assay the expression of hsa-miR-1269a and FAM46C in ESCC cells. The results showed that hsa-miR-1269a was upregulated in ESCC tissues and cell lines. Hsa-miR-1269a overexpression stimulated the proliferation, migration, and invasion capacities of ESCC cells, and FAM46C overexpression inhibited these phenotypes. Dual-luciferase assay verified that hsa-miR-1269a could target FAM46C. Next, qRT-PCR and western blot demonstrated that hsa-miR-1269a overexpression downregulated FAM46C. Rescue experiments revealed that hsa-miR-1269a accelerated the malignant progression of ESCC through FAM46C down-regulation. These results indicate that the interaction between hsa-miR-1269a and FAM46C plays a regulatory role in driving the malignant progression of ESCC cells, thereby providing a novel molecular mechanism for understanding ESCC.

Diosmetin suppresses the progression of ESCC by CDK2/Rb/E2F2/RRM2 pathway and synergies with cisplatin.

Cisplatin (CDDP) is the first-line drug in the clinical treatment of esophageal squamous cell carcinoma (ESCC), which has severe nephrotoxicity. Diosmetin (DIOS) can protect kidney from oxidative damage, however, its function in ESCC is unknown. This study aims to explore the effect and mechanism of DIOS on ESCC and its combined effect with CDDP. Herein, we found that DIOS significantly inhibited the progression of ESCC in vitro and in vivo. Furthermore, the anti-tumor effect of DIOS was not statistically different from that of CDDP. Mechanically, transcriptomics revealed that DIOS inhibited the E2F2/RRM2 signaling pathway. The transcriptional regulation of RRM2 by E2F2 was verified by luciferase assay. Moreover, docking model, CETSA, pull-down assay and CDK2 inhibitor assay confirmed that DIOS directly targeted CDK2, leading to significant suppression of ESCC. Additionally, the patient-derived xenografts (PDX) model showed that the combination of DIOS and CDDP significantly inhibited the growth of ESCC. Importantly, the combined treatment with DIOS and CDDP significantly reduced the mRNA expression levels of kidney injury biomarkers KIM-1 and NGAL in renal tissue, as well as the levels of blood urea nitrogen, serum creatinine and blood uric acid compared to the single treatment with CDDP. In conclusion, DIOS could be an effective drug and a potential chemotherapeutic adjuvant for ESCC treatment. Furthermore, DIOS could reduce the nephrotoxicity of CDDP to some extent.

Linc01614 Regulates the Proliferation, Apoptosis, and Chemotherapy Resistance in Esophageal Squamous Cell Carcinoma by Targeting Mir-4775.

Esophageal squamous cell carcinoma (ESCC), a widely known esophageal disease, severely affects people's health. Numerous investigations demonstrated that long non-coding RNAs (lncRNAs) performed key jobs inside a wide scope of organic cycles and stand out in malignant growth. Our study planned to investigate the roles and mechanisms of linc01614 in ESCC. A Total of 60 ESCC tissue samples including 30 patients with cisplatin sensitivity and 30 patients with cisplatin resistance, who received DDP-based treatment, were obtained from Zhuhai People's Hospital, Zhuhai City during 2021. These tissues were frozen and saved in a -80 °C ultra-low temperature freezer. We performed CCK-8, clone formation, flow cytometry assays to determine the effect of linc01614 on ESCC progression, and explored the specific mechanism of linc01614 in ESCC cell proliferation, apoptosis, and chemotherapy resistance. linc01614 expression was upregulated in ESCC tissues and cells compared with non-tumor tissues and human normal esophageal epithelial cells (Het-1A). Knockdown of linc01614 repressed cell expansion, chemotherapy opposition, and advanced cell apoptosis in ESCC. Besides, linc01614 regulated the expression of miR-4775 as a competitive endogenous RNA (ceRNA). The linc01614/miR-4775 axis played an important role in ESCC progression and drug resistance, revealing that linc01614 is a promising target in ESCC treatment.

SLC43A2 and NFκB signaling pathway regulate methionine/cystine restriction-induced ferroptosis in esophageal squamous cell carcinoma via a feedback loop

Studies have indicated dietary restriction of methionine/cystine provided a therapeutic benefit in diseases such as cancer. However, the molecular and cellular mechanisms that underlie the interaction between methionine/cystine restriction (MCR) and effects on esophageal squamous cell carcinoma (ESCC) have remained elusive. Here, we discovered the dietary restriction of methionine/cystine has a large effect on cellular methionine metabolism as assayed in a ECA109 derived xenograft model. RNA-seq and enrichment analysis suggested the blocked tumor progression was affected by ferroptosis, together with the NFκB signaling pathway activation in ESCC. Consistently, GSH content and GPX4 expression were downregulated by MCR both in vivo and in vitro. The contents of Fe2+ and MDA were negatively correlated with supplementary methionine in a dose-dependent way. Mechanistically, MCR and silent of SLC43A2, a methionine transporter, diminished phosphorylation of IKKα/β and p65. Blocked NFκB signaling pathway further decreased the expression of SLC43A2 and GPX4 in both mRNA and protein level, which in turn downregulated the methionine intake and stimulated ferroptosis, respectively. ESCC progression was inhibited by enhanced ferroptosis and apoptosis and impaired cell proliferation. In this study, we proposed a novel feedback regulation mechanism underlie the correlation between dietary restriction of methionine/cystine and ESCC progression. MCR blocked cancer progression via stimulating ferroptosis through the positive feedback loop between SLC43A2 and NFκB signaling pathways. Our results provided the theoretical basis and new targets for ferroptosis-based clinical antitumor treatments for ESCC patients.

RPS15 interacted with IGF2BP1 to promote esophageal squamous cell carcinoma development via recognizing m6A modification

Increased rates of ribosome biogenesis have been recognized as hallmarks of many cancers and are associated with poor prognosis. Using a CRISPR synergistic activation mediator (SAM) system library targeting 89 ribosomal proteins (RPs) to screen for the most oncogenic functional RPs in human esophageal squamous cell carcinoma (ESCC), we found that high expression of RPS15 correlates with malignant phenotype and poor prognosis of ESCC. Gain and loss of function models revealed that RPS15 promotes ESCC cell metastasis and proliferation, both in vitro and in vivo. Mechanistic investigations demonstrated that RPS15 interacts with the K homology domain of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), which recognizes and directly binds the 3′-UTR of MKK6 and MAPK14 mRNA in an m6A-dependent manner, and promotes translation of core p38 MAPK pathway proteins. By combining targeted drug virtual screening and functional assays, we found that folic acid showed a therapeutic effect on ESCC by targeting RPS15, which was augmented by the combination with cisplatin. Inhibition of RPS15 by folic acid, IGF2BP1 ablation, or SB203580 treatment were able to suppress ESCC metastasis and proliferation via the p38 MAPK signaling pathway. Thus, RPS15 promotes ESCC progression via the p38 MAPK pathway and RPS15 inhibitors may serve as potential anti-ESCC drugs.

Predicting role of circulating tumor DNA and blood-based tumor mutational burden in esophageal squamous cell carcinoma receiving chemoradiotherapy combined with toripalimab: Exploratory analyses from a phase II trial (EC-CRT-001).

4056 Background: EC-CRT-001 is a phase II trial investigating the efficacy of toripalimab (an anti-PD1 antibody) combined with definitive chemoradiotherapy (CRT) in locally advanced esophageal squamous cell carcinoma (ESCC) and the results demonstrated encouraging antitumor activity and acceptable toxicity. This exploratory analysis was performed to evaluate the role of circulating tumor DNA (ctDNA) and blood-based tumor mutational burden (bTMB) for efficacy prediction. Methods: Forty-two patients from the phase II trial (NCT04005170) who received toripalimab (240 mg every 3 weeks for up to 1 year, or disease progression, or unacceptable toxicity) combined with definitive CRT (irradiation with 50.4 Gy in 28 fractions concurrent with 5 cycles of weekly paclitaxel in 50 mg/m2 and cisplatin in 25 mg/m2) were enrolled. Plasma samples were collected before, during, and after CRT. Targeted next-generation sequencing was performed on a total of 118 plasma samples and 35 matched tumor samples using a panel covering 474 cancer-associated genes. Results: Twenty-six (62%) of 42 patients achieved clinical complete response (cCR) at three months after CRT. ctDNA was detected in 29 (72.5%) of 40 patients at baseline. The positive rate of ctDNA decreased to 43.9% (20/41) during CRT and continued to descend to 27.0% (10/37) at the completion of CRT. A higher cCR rate was observed in patients with negative during-CRT ctDNA compared to those with detectable ctDNA (82.6% vs. 38.9%, P = 0.008). Patients with post-CRT detectable ctDNA also had poorer cCR rate (30.0% vs. 77.8%, P = 0.017). Within a median follow-up of 24.0 months (IQR 13.7-27.9), the median progression-free survival (PFS) was 12.2 months (95%CI: 8.4-16.0) and median overall survival (OS) was not reached for the whole cohort. Patients with during-CRT detectable ctDNA had shorter PFS compared to ctDNA-negative patients (HR = 2.57, 95%CI: 1.18-5.60, P = 0.014). Similarly, patients with post-CRT detectable ctDNA also had a significantly increased risk of disease progression (HR = 2.88, 95%CI: 1.21-6.83, P = 0.012) and death (HR = 3.67, 95%CI: 1.41-9.55, P = 0.004). Moreover, patients with higher bTMB ( > 1) detected during CRT were associated with a favorable OS (HR = 0.33, 95%CI: 0.13-0.88, P = 0.027). Improved PFS was also observed in those patients with higher post-CRT bTMB ( > 3) (HR = 0.28, 95%CI: 0.08-0.96, P = 0.042). Conclusions: Negative ctDNA status and higher bTMB during or after CRT were associated with better tumor response and favorable survival in ESCC patients who underwent definitive CRT combined with toripalimab. Dynamic ctDNA has great potential in predicting efficacy and risk of disease progression in ESCC. Clinical trial information: NCT04005170 .

Hypoxia-responsive lncRNA G077640 promotes ESCC tumorigenesis via the H2AX-HIF1α-glycolysis axis.

Long noncoding RNAs (lncRNAs) contribute to esophageal squamous cell carcinoma (ESCC) progression, but the underlying mechanisms remain elusive. In this study, we verified a hitherto uncharacterized hypoxia-responsive lncRNA, G077640, which is upregulated in human ESCC cells and tissues, supporting the proliferation and migration of ESCC cells. Mechanistically, G077640 prevented hypoxia-inducible factor-1α (HIF1α) from being degraded by directly interacting with histone H2AX and further modulated the interaction of HIF1α and H2AX. In addition, G077640 reprogrammed glycolytic metabolism by regulating the expression of glucose transporter 4 (GLUT4), hexokinase 2 (HK2) and pyruvate dehydrogenase kinase 1 (PDK1) for ESCC proliferation and migration. Clinically, G077640 was associated with poor prognosis in ESCC patients. Taken together, our findings identified a hypoxia-responsive lncRNA that contributes to ESCC cells proliferation and migration, and targeting G077640 and its pathway might be a potential therapeutic strategy for ESCC.

Homeobox A7 promotes esophageal squamous cell carcinoma progression through C-C motif chemokine ligand 2-mediated tumor-associated macrophage recruitment.

Homeobox A7 (HOXA7) plays essential roles in multiple malignancies and was reported to be overexpressed in esophageal squamous cell carcinoma (ESCC). However, its functions in the ESCC tumor microenvironment remain to be explored. In this study, we showed that HOXA7 was overexpressed in ESCC among HOXA family members and correlated with tumor-associated macrophage (TAM) infiltration both in The Cancer Genome Atlas database and ESCC clinical samples. Moreover, transactivation of C-C motif chemokine ligand 2 (CCL2) by HOXA7 was identified (real-time quantitative PCR [RT-qPCR], western blot analysis, ELISA, and ChIP-qPCR), which was detected to drive chemotaxis and M2 polarization of macrophages both in vitro (Transwell assay) and in vivo (xenograft tumors models). In addition, CCL2 triggers macrophage expression of epidermal growth factor (EGF) (RT-qPCR and ELISA), which promotes tumor proliferation and metastasis by activating its receptor EGFR. In addition, EGF-induced ESCC cell proliferation and migration can be abrogated by HOXA7 knockdown (CCK-8 proliferation assay, EdU fluorescence, and Transwell assay). These results indicate a novel mechanistic role of HOXA7 in the cross-talk between ESCC and TAMs, which could be an underlying therapeutic target for ESCC.

RNF106 aggravates esophageal squamous cell carcinoma progression through LATS2/YAP axis

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal solid tumors in China, with the 5-year overall survival rate less than 20%. Although the carcinogenic process of ESCC is still not clear, recent studies using whole genomic profiling revealed that dysregulation of Hippo signaling pathway might play important roles in ESCC progression. The ubiquitin-like with PHD and RING finger domain 1 (RNF106) was a modifier of DNA methylation and histone ubiquitination. In this study, we evaluate the oncogenic function of RNF106 in ESCC both in vitro and in vivo. Wound healing and transwell data showed that RNF106 was required for ESCC cell migration and invasion. RNF106 depletion dramatically restrained Hippo signaling targeted gene expression. The bioinformatics analysis displayed that RNF106 was increased in ESCC tumor tissues and related with poor survival in ESCC patients. Mechanistic studies demonstrated that RNF106 was associated with LATS2 and facilitate LATS2 K48-linked ubiquitination and degradation, which subsequently inhibited YAP phosphorylation and promoted YAP oncogenic function in ESCC. Taken together, our study revealed a novel link between RNF106 and Hippo signaling in ESCC, suggesting that RNF106 could be a promising target for ESCC therapy.

Aprepitant inhibits the progression of esophageal squamous cancer by blocking the truncated neurokinin‑1 receptor.

Increasing evidence showed that the substance P (SP)/neurokinin‑1 receptor (NK1R) complex is involved in the development of several cancers. However, little is known about the mechanisms by which SP/NK1R complex plays a role in esophageal squamous cell carcinoma (ESCC) progression. RT‑qPCR, CCK‑8, Transwell, western blotting, immunohistochemical, immunofluorescence, ELISA and analysis of apoptosis were employed in the present study. It was aimed to investigate the function and therapeutic potential of the SP/tr‑NK1R system in human ESCC progression. The results revealed that both SP and tr‑NK1R were highly expressed in ESCC cell lines and specimens. In ESCC tissues, SP was mainly derived from ESCC cells and M2 macrophages. The NK1R antagonist aprepitant inhibited the SP‑induced proliferation of human ESCC cell lines. Aprepitant inhibited cell migration and invasion and induced apoptosis of ESCC cells by downregulating the PI3K/AKT/mTOR signaling pathways. Animal experiments revealed that aprepitant inhibited tumor progression of ESCC in xenograft mice. In conclusion, high expression of SP plus tr‑NK1R indicated poor prognosis in ESCC, suggesting that aprepitant has a potential application in ESCC. To the best of our knowledge, high SP and tr‑NK1R expression in ESCC cell lines was reported for the first time in the present study. These findings provided evidence for a novel therapeutic strategy for patients with ESCC.

DUSP4 promotes esophageal squamous cell carcinoma progression by dephosphorylating HSP90β

The molecular and pathogenic mechanisms of esophageal squamous cell carcinoma (ESCC) development are still unclear, which hinders the development of effective treatments. In this study, we report that DUSP4 is highly expressed in human ESCC and is negatively correlated with patient prognosis. Knockdown of DUSP4 suppresses cell proliferation and patient-derived xenograft (PDX)-derived organoid (PDXO) growth and inhibits cell-derived xenograft (CDX) development. Mechanistically, DUSP4 directly binds to heat shock protein isoform β (HSP90β) and promotes the ATPase activity of HSP90β by dephosphorylating HSP90β on T214 and Y216. These dephosphorylation sites are critical for the stability of JAK1/2-STAT3 signaling and p-STAT3 (Y705) nucleus translocation. Invivo, Dusp4 knockout in mice significantly inhibits 4-nitrochinoline-oxide-induced esophageal tumorigenesis. Moreover, DUSP4 lentivirus or treatment with HSP90β inhibitor (NVP-BEP800) significantly impedes PDX tumor growth and inactivates the JAK1/2-STAT3 signaling pathway. These data provide insight into the role of the DUSP4-HSP90β-JAK1/2-STAT3 axis in ESCC progression and describe a strategy for ESCC treatment.

Clinicopathological relevance of stem cell marker growth and differentiation factor 3 in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is the second leading cause of cancer-related deaths in Iran, often diagnosed in advanced stages with a poor prognosis. Growth and differentiation factor 3 (GDF3) is a member of the transforming growth factor-beta (TGF-β) superfamily. It acts as an inhibitor of bone morphogenetic proteins (BMPs) signaling pathway associated with pluripotent embryonic and cancer stem cells (CSCs) characteristics. Since its expression in ESCC has not yet been evaluated, the clinicopathological relevance of GDF3 expression was elucidated in ESCC patients. Expression of GDF3 in tumor tissues from 40 ESCC patients was compared to the related margin normal tissues by relatively comparative real-time polymerase chain reaction (PCR). Glyceraldehydes 3-phosphate dehydrogenase (GAPDH) was used as the endogenous control. Likewise, the function of GDF3 in the differentiation and development of embryonic stem cells (ESCs) was also reviewed. GDF3 was significantly overexpressed in 17.5% of tumors and a significant correlation between GDF3 expression and the depth of tumor invasion was observed (P = 0.032). The results suggest that GDF3 expression is likely to have substantial roles in the progression and invasiveness behavior of ESCC. Having considered the importance of CSC markers identification and their exploitation in targeted cancer therapy, GDF3 may be introduced as a promising therapeutic target to inhibit the invasion of tumor cells in ESCC.

Bioinformatics and experimental validation of an AURKA/TPX2 axis as a potential target in esophageal squamous cell carcinoma.

Aurora kinase A (AURKA), a serine/threonine kinase that regulates mitotic processes, has garnered significant interest given its association with the development of several types of cancer. In the present study, it was shown that AURKA expression was significantly upregulated in esophageal squamous cell carcinoma (ESCC) and could serve as a diagnostic and prognostic indicator based on data obtained from The Cancer Genome Atlas (TCGA) and immunohistochemical analysis. In addition, AURKA was functionally associated with ESCC cell proliferation and colony formation invitro and knockdown of AURKA inhibited ESCC tumor growth invivo. Both bioinformatics analysis and pull‑down assays demonstrated that TPX2 interacted with AURKA, and their expression was correlated. AURKA cooperated with TPX2 to regulate ESCC progression via the PI3K/Akt pathway. Furthermore, AURKA or TPX2 expression levels were negatively associated with the infiltration of cytotoxic cells, CD8+ T cells and mast cells, but positively associated with Th2 cells. The present study provided a relatively comprehensive understanding of the oncogenic roles of AURKA in ESCC based on data obtained from TCGA combined with experimental analysis.

CircABCA13 acts as a miR-4429 sponge to facilitate esophageal squamous cell carcinoma development by stabilizing SRXN1.

Circular RNAs (circRNAs) play a pivotal role in the tumorigenesis and progression of various cancers. However, the role and mechanisms of circABCA13 in esophageal squamous cell carcinoma (ESCC) are largely unknown. Here, we reported that circABCA13, a novel circular RNA generated by back-splicing of the intron of the ABCA13 gene, is highly expressed in ESCC tumor tissues and cell lines. Upregulation of circABCA13 correlated with TNM stage and a poor prognosis in ESCC patients. While knockdown of circABCA13 in ESCC cells significantly reduced cell proliferation, migration, invasion, and anchorage-independent growth, overexpression of circABCA13 facilitated tumor growth both in vitro and in vivo. In addition, circABCA13 directly binds to miR-4429 and sequesters miR-4429 from its endogenous target, SRXN1 mRNA, which subsequently upregulates SRXN1 and promotes ESCC progression. Consistently, overexpression of miR-4429 or knockdown of SRXN1 abolished malignant behavior promotion of ESCC results from circABCA13 overexpression in vitro and in vivo. Collectively, our study uncovered the oncogenic role of circABCA13 and its mechanism in ESCC, suggesting that circABCA13 could be a potential therapeutic target and a predictive biomarker for ESCC patients.

All-Trans Retinoic Acid Promotes a Tumor Suppressive OTUD6B-β-TrCP-SNAIL Axis in Esophageal Squamous Cell Carcinoma and Enhances Immunotherapy.

β-TrCP is an E3 ubiquitin ligase that plays important roles in multiple human cancers including esophageal squamous cell carcinoma (ESCC). Analysis of ESCC patient samples reveal that only protein level but not transcript level of β-TrCP associated with patient prognosis, suggesting regulators of β-TrCP protein stability play an essential role in ESCC progression and may be novel targets to develop ESCC therapies. Although β-TrCP stability is known to be mediated by the ubiquitin-proteasome system, it is unclear which enzymes play a major role to determine β-TrCP stability in the context of ESCC. In this study, OTUD6B is identified as a potent deubiquitinase of β-TrCP that suppress ESCC progression through the OTUD6B-β-TrCP-SNAIL axis. Low OTUD6B expression is associated with a poor prognosis of ESCC patients. Importantly, all-trans retinoic acid (ATRA) is found to promote OTUD6B translation and thus suppress ESCC tumor growth and enhance the response of ESCC tumors to anti-PD-1 immunotherapies. These findings demonstrate that OTUD6B is a crucial deubiquitinase of β-TrCP in ESCC and suggest combination of ATRA and anti-PD-1 immune checkpoint inhibitor may benefit a cohort of ESCC patients.

Mutant p53 activates hnRNPA2B1-AGAP1-mediated exosome formation to promote esophageal squamous cell carcinoma progression

p53 mutations predispose cancer cell development, promote their survival and metastasis, and lead to ineffective therapeutic responses and unfavorable prognosis. No drug that abrogates the oncogenic functions of mutant p53 has been approved for cancer treatment. Here, we performed whole-genome sequencing of 663 esophageal squamous cell carcinoma (ESCC) tumor tissues and paired normal tissues. The results indicated that ESCC samples from our cohort had a more dispersed distribution of TP53 mutants and a higher proportion of nonsense mutants than European and American ESCC samples in the International Agency for Research on Cancer (IARC) database. The most frequent p53 mutations disrupt the inhibition of proliferation, migration, and invasion mediated by wild-type p53 in ESCC. Furthermore, p53 mutations alter its protein nucleoplasmic localization and protein stability. The p53 mutation G245S (p53-G245S) interacts with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) to increase protein translation of phosphatidylinositol-dependent Arf GAP (AGAP1) by promoting AGAP1 mRNA stability. AGAP1 promotes cancer cell proliferation and metastasis by enhancing exosome formation. Furthermore, we explored the combination of the HSP90 inhibitor HSP90i and the AGAP1 inhibitor QS11 could inhibit ESCC cell proliferation and metastasis. Thus, the p53-G245S/hnRNPA2B1/AGAP1 axis promotes ESCC progression by enhancing exosome formation, and the combination of an HSP90 inhibitor and an AGAP1 inhibitor may serve as a potential therapeutic strategy.

Microbial and epidemiological factors in early detection of esophageal squamous cell carcinoma and precancerous lesions.

Microbial and epidemiological factors in early detection of esophageal squamous cell carcinoma and precancerous lesions.