Paired-related homeobox 1 induces epithelial-mesenchymal transition in oesophageal squamous cancer

BACKGROUND It is unclear that paired-related homeobox 1(PRRX1)induces epithelialmesenchymal transition(EMT)in oesophageal cancer and the specific function of PRRX1 in oesophageal cancer metastasis.AIM To assess the signicance of PRRX1 expression and investigate the mechanism of EMT in oesophageal cancer metastasis.METHODS Detect the expression of PRRX1 by immunohistochemistry in oesophageal tumour tissues and adjacent normal oesophageal tissues;the PRRX1 short hairpin RNA(shRNA)or blank vector lentiviral gene delivery system was transfected into cells;cell proliferation assay,soft agar colony formation assays,cell invasion and migration assays and animal studies were used to observe cells biological characteristics In vitro and in vivo;XAV939 and LiCl were used to alter the activity of Wnt/β-catenin pathway.Immunofluorescence staining and western blot analysis were used to detect protein expression of EMT markers and Wnt/β-catenin pathway.RESULTS PRRX1 is expressed at high levels in oesophageal cancer specimens and is closely related to tumour metastasis in patients with oesophageal cancer.Regulation of PRRX1 expression might exert obvious effects on cell proliferation,especially the migration and invasion of oesophageal cancer cells.Moreover,silencing PRRX1 expression using a shRNA produced the opposite effects.In addition,when PRRX1 was overexpressed,inhibition of the Wnt/β-catenin pathway with XAV939 negated the effect of PRRX1 on EMT,whereas when PRRX1 was downregulated,activation of the Wnt/β-catenin pathway with LiCl impaired the effect on EMT.CONCLUSION PRRX1 is upregulated in oesophageal cancer is closely correlated with cancer metastasis.Additionally,PRRX1 induces EMT in oesophageal cancer metastasis through activation of Wnt/β-catenin signalling.

Linked color imaging vs Lugol chromoendoscopy for esophageal squamous cell cancer and precancerous lesion screening: A noninferiority study

BACKGROUND Lugol chromoendoscopy(LCE)has served as a standard screening technique in high-risk patients with esophageal cancer.Nevertheless,LCE is not suitable for general population screening given its side effects.Linked color imaging(LCI)is a novel image-enhanced endoscopic technique that can distinguish subtle differences in mucosal color.AIM To compare the diagnostic performance of LCI with LCE in detecting esophageal squamous cell cancer and precancerous lesions and to evaluate whether LCE can be replaced by LCI in detecting esophageal neoplastic lesions.METHODS In this prospective study,we enrolled 543 patients who underwent white light imaging(WLI),LCI and LCE successively.We compared the sensitivity and specificity of LCI and LCE in the detection of esophageal neoplastic lesions.Clinicopathological features and color analysis of lesions were assessed.RESULTS In total,43 patients(45 neoplastic lesions)were analyzed.Among them,36 patients(38 neoplastic lesions)were diagnosed with LCI,and 39 patients(41 neoplastic lesions)were diagnosed with LCE.The sensitivity of LCI was similar to that of LCE(83.7%vs 90.7%,P=0.520),whereas the specificity of LCI was greater than that of LCE(92.4%vs 87.0%,P=0.007).The LCI procedure time in the esophageal examination was significantly shorter than that of LCE[42(34,50)s vs 160(130,189)s,P<0.001].The color difference between the lesion and surrounding mucosa in LCI was significantly greater than that observed with WLI.However,the color difference in LCI was similar in different pathological types of esophageal squamous cell cancer.CONCLUSION LCI offers greater specificity than LCE in the detection of esophageal squamous cell cancer and precancerous lesions,and LCI represents a promising screening strategy for general populations.

Three novel rare TP53 fusion mutations in a patient with multiple primary cancers:a case report

As survival rates improve and detection technologies advance,the occurrence of multiple primary cancers(MPCs)has been increasing.Approximately 16%of cancer survivors develop a subsequent malignancy,with lung cancer often developing after esophageal cancer due to potential“field cancerization”effects.Despite this observation,the genetic heterogeneity underlying MPCs remains understudied.However,the recent emergence of genetic testing has expanded the scope of investigations into MPCs to investigate signatures underlying cancer predisposition.This report reveals 3 unprecedented TP53 fusion mutations in a Chinese patient afflicted by MPCs,namely,AP1M2–TP53(A1;T11)fusion,TP53–ILF3(T10;I13)fusion,and SLC44A2–TP53(S5;T11)fusion.This patient exhibited an extended period of survival after diagnosis of extensive-stage small cell lung cancer,which occurred 6 years after the diagnosis of esophageal squamous cell cancer.This unique reportmay provide supplementary data that enhance our understanding of the genetic landscape ofMPCs.

Inhibition of squamous cancer growth in a mouse model by Staphylococcal enterotoxin B-triggered Th9 cell expansion

Currently, therapy for squamous cancer （SqC） is unsatisfactory. Staphylococcal enterotoxin B （SEB） has strong immune regulatory activity. This study tests the hypothesis that SEB enforces the effect of immunotherapy on SqC growth in a mouse model. C3H/HeN mice and the SqC cell line squamous cell carcinoma VII were used to create an SqC mouse model. Immune cell assessment was performed by flow cytometry. Real-time RT-PCR and western blotting were used to evaluate target molecule expression. An apoptosis assay was used to assess the suppressive effect of T helper-9 （Th9） cells on the SqC cells. The results showed that immunotherapy consisting of SEB plus SqC antigen significantly inhibited SqC growth in the mice. The frequency of Th9 cells was markedly increased in the SqC tissue and mouse spleens after treatment. SEB markedly increased the levels of signal transducer and activator of transcription 5 phosphorylation and the expression of histone deacetylase-1 （HDAC1） and PU.1 （the transcription factor of the interleukin 9 （IL-9） gene） in CD4^＋ T cells. Exposure to SqC-specific Th9 cells markedly induced SqC cell apoptosis both in vitro and in vivo. In conclusion, the administration of SEB induces Th9 cells in SqC-bearing mice, and theseTh9 cells inhibit SqC growth.

Use of Holmium:Yag laser in early stage oropharyngeal squamous cell cancer

AIM: To evaluate the efficacy of Holmium:Yag laser resection for oropharyngeal squamous cell cancer.METHODS: A prospectively collected case series of all patients with oropharyngeal squamous cell carcinoma undergoing laser resection using the Holmium:Yag laser technique only over a 15 year period at a tertiary referral centre. All patients underwent long term follow up with regular clinical and radiological surveillance, when indicated. All patients were operated on under general anaesthetic with a laser-safe endotracheal tube. Typically laser resection was performed first using an operating microscope, followed by neck dissection. The tumour was held with a Luc's forceps or Allis clamp. The Holmium:Yag laser was implemented via a fibre delivery system. The Holmium:Yag laser fibre, of 550 micron diameter, was inserted through a Zoellner sucker and attached via steri-strips to a second Zoellner suction to provide smoke evacuation. The settings were 1J/pulse, 15 Hz, 15 W in a continuous delivery modality via a foot pedal control. The procedure is simple, bloodless, effective and quick. All surgeries were performed as day cases. RESULTS: Twenty-seven oropharyngeal squamous cell cancer patients were identified, at the following subsites:23 lateral pharyngeal wall/tonsil, 2 anterior faucal and 2 tongue base. Of the 23 tonsil tumours,19 required no further treatment(83% therefore had negative histopathological margins) and 4 required chemoradiotherapy(17% were incompletely excised or had aggressive histopathological features such as discohesive, perineural spread, vascular invasion). The 2 patients with anterior faucal pillar neoplasia needed no further treatment. Both tongue base cancer cases required further treatment in the form of chemoradiotherapy(due to positive histopathological margins). Postoperatively, patients complained of pain locally, which resolved with regular analgesia. There were no postoperative haemorrhages. Swallowing and speech were normal after healing(10-14 d). There was one case of fistula when neck dissection was carried out simultaneously; this resolved with conservative management. All patients were followed up with serial imaging and clinical examination for a minimum of five years. Median follow up was 84 mo.CONCLUSION: Holmium:Yag lasers are a safe and effective treatment for Stage 1 and 2 squamous cell carcinoma of the oropharynx, excluding the tongue base.

ROS1 in Squamous Non-Small Cell Lung Cancer—Combined Immunotherapy (PD1/CTLA4) or Targeted Therapy?

ROS1 oncogenic fusion is reported to be 1% - 2% of non-small cell lung cancers (NSCLCs) of the adenocarcinoma subgroup. Meanwhile, there are no records of squamous cell cancer patients with tumors harboring ROS1 fusions. The Foundation Medicine database indicates a frequency of ROS1 rearrangements is 0.2% among squamous NSCLC. Crizotinib is known to be very effective in these patients. Here we present a non-smoker patient who had pure squamous NSCLC that was treated by combinational immunotherapy under a clinical trial and progressed after 2 cycles. Surprisingly, comprehensive genomic profiling detected a rare oncogenic EZR-ROS1 fusion, and the patient was treated by crizotinib with a significant response within 6 weeks. To date, the patient has been on therapy for 42 months and has achieved a complete metabolic response.

Anal Invasive Squamous Cell Cancer and Human Papillomavirus Distribution in HIV-Infected and Non-HIV-Infected Individuals

Invasive-squamous-cell-cancer (ISCC) of the anal canal is an uncommon disease. Human papillomavirus (HPV) is the etiological agent of most of types of ISCC. The incidence of ISCC has been increasing in HIV-infected individuals, even after the introduction of highly active antiretroviral therapy. The aim of this study was to analyze biopsy specimens from patients diagnosed with ISCC at a tertiary hospital from 1983 to 2012 in order to detect HPV-DNA. Methods: Formaldehyde-fixed, paraffin-embedded specimens from patients with ISCC underwent HPV-DNA genotyping using multiplex PCR assay. Results: A total of 31 cases were collected;10 were HIV-infected (9 men, 1 woman) and 21 non-HIV-infected (11 men, 10 women). HPV infection was detected in 87.5% (7/8) of the HIV-infected patients (DNA from 2 biopsies was degraded) and 76.2% (16/21) of non-HIV-infected individuals. Multiple-type infections were only found in 28.6% (2/7) of the HIV-infected patients (no multiple-type infections in non-HIV-infected individuals). The most prevalent type was HPV-16: 50% (4/8) in the HIV-infected group (57% [4/7] of the HPV-positive samples) and 66.7% (14/21) in the non-HIV-infected group (87.5% (14/16) of the HPV-positive samples). Remarkably, 37.5% (3/8) of the HIV-infected group had high-risk HPV types not included in the vaccines (HPV-33, 51, 52, and 66) compared with 4.8% in the non-HIV-infected group (1/21, HPV-52). All cases of anal ISCC in HIV-infected patients were recorded in the highly active antiretroviral therapy era. Conclusion: HIV-infected patients presented anal ISCC with a higher proportion of high-risk HPV types not covered by the conventional vaccines than non-HIV-infected individuals.

Rapid killer:Lung squamous cell cancer

Background:Lung cancer is one of the leading causes of death despite improvement in treatment modalities such as immunotherapy with chemotherapy and precise radiotherapy.NSCLC is a heterogeneous group of diseases that differs in cytology and includes adenocarcinoma,squamous cell carcinoma,bronchioloalveolar carcinoma,and poorly differentiated carcinoma.Usually,NSCLC,in contrast to SCLC,spreads locally,and the doubling time of squamous cell carcinoma is 133 days which classifies it as a relatively slow-growing tumor.Case presentation:We present the case of a 72-year-old male,recently diagnosed with squamous cell carcinoma in the right upper lobe along with secondary deposits.Few days after diagnosis,the patient had severe respiratory distress.This endobronchial tumor has increased significantly in size upon bronchoscopic visualization causing a complete obstruction of his right main bronchus and hypoxemic respiratory failure requiring intubation.Conclusion:To our knowledge,there are few reported cases where lung adenocarcinoma progressed rapidly over days.Squamous cell carcinoma usually takes 3 to 6 months to double in size,but in our case,the progression was very fast.In the last decade,it was confirmed that the doubling time of a tumor is an independent factor in the prognosis of lung cancer patients.On the other hand,further studies are needed to identify genes associated with rapid progression and a worse prognosis for lung squamous cell carcinoma.Hence,this aggressive tumor is a“rapid killer.”

Artificial intelligence-assisted esophageal cancer management:Now and future

Esophageal cancer poses diagnostic,therapeutic and economic burdens in highrisk regions.Artificial intelligence(AI)has been developed for diagnosis and outcome prediction using various features,including clinicopathologic,radiologic,and genetic variables,which can achieve inspiring results.One of the most recent tasks of AI is to use state-of-the-art deep learning technique to detect both early esophageal squamous cell carcinoma and esophageal adenocarcinoma in Barrett’s esophagus.In this review,we aim to provide a comprehensive overview of the ways in which AI may help physicians diagnose advanced cancer and make clinical decisions based on predicted outcomes,and combine the endoscopic images to detect precancerous lesions or early cancer.Pertinent studies conducted in recent two years have surged in numbers,with large datasets and external validation from multi-centers,and have partly achieved intriguing results of expert’s performance of AI in real time.Improved pre-trained computer-aided diagnosis algorithms in the future studies with larger training and external validation datasets,aiming at real-time video processing,are imperative to produce a diagnostic efficacy similar to or even superior to experienced endoscopists.Meanwhile,supervised randomized controlled trials in real clinical practice are highly essential for a solid conclusion,which meets patient-centered satisfaction.Notably,ethical and legal issues regarding the blackbox nature of computer algorithms should be addressed,for both clinicians and regulators.

Predicting malignant transformation of esophageal squamous cell lesions by combined biomarkers in an endoscopic screening program

AIM To determine the association of p53, carcinoembryonic antigen(CEA) and CA19-9 protein expression with esophageal carcinogenesis.METHODS An iodine staining endoscopic screening program of esophageal lesions was carried out in the high-incidence area of Feicheng County, China. Seventy-seven patients with basal cell hyperplasia(BCH), 247 with low-grade dysplasia(LGD), 51 with high-grade dysplasia(HGD), 134 with invasive cancer, and 80 normal controls diagnosed by mucous membrane biopsy pathology were enrolled. Immunohistochemical detection of p53, CEA and CA19-9 proteins was performed. In the ROCcurve analysis, the expression of a single biomarker and the expression of a combination of biomarkers were used to predict the risk of these four esophageal lesions.RESULTS The positive rates of p53 protein expression in invasive cancer, HGD, LGD, BCH and the normal control groups were 53.0%, 52.9%, 35.6%, 27.3% and 20.0%, respectively; the positive rates of CA19-9 protein expression were 44.0%, 33.3%, 16.5%, 9.2% and 6.2%, respectively; the positive rates of CEA protein expression were 74.6%, 60.8%, 23.3%, 23.7% and 16.2%, respectively. The positive rates of the combined expression of the three biomarkers were 84.3%, 76.5%, 47.6%, 42.9% and 27.5%, respectively. In the receiver operating characteristic curves of the combination of the three biomarkers, the specificity was 88.8% for the normal controls, and the sensitivity was 58.2% for invasive cancer, 25.5% for HGD, 11.2% for LGD, and 6.5% for BCH.CONCLUSION p53, CEA and CA19-9 protein expression was correlated with esophageal carcinogenesis, and testing for the combination of these biomarkers is useful for identifying high-risk patients with precancerous lesions.

Prognostic and incremental value of computed tomography-based radiomics from tumor and nodal regions in esophageal squamous cell carcinoma

Objective:This study aimed to evaluate the prognostic value of preoperative radiomics and establish an integrated model for esophageal squamous cell cancer(ESCC).Methods:A total of 931 patients were retrospectively enrolled in this study(training cohort,n=624;validation cohort,n=307).Radiomics features were obtained by contrast-enhanced computed tomography(CT)before esophagectomy.A radiomics index was set based on features of tumor and reginal lymph nodes by using the least absolute shrinkage and selection operator(LASSO)Cox regression.Prognostic nomogram was built based on radiomics index and other independent risk factors.The prognostic value was assessed by using Harrell’s concordance index,time-dependent receiver operating characteristics and Kaplan-Meier curves.Results:Twelve radiomic features from tumor and lymph node regions were identified to build a radiomics index,which was significantly associated with overall survival(OS)in both training cohort and validation cohort.The radiomics index was highly correlated with clinical tumor-node-metastasis(cTNM)and pathologic TNM(pTNM)stages,but it demonstrated a better prognostic value compared with cTNM stage and was almost comparable with pTNM stage.Multivariable Cox regression showed that the radiomics index was an independent prognostic factor.An integrated model was constructed based on gender,preoperative serum sodium concentration,pTNM and the radiomics index for clinical usefulness.The integrated model demonstrated discriminatory ability better compared with the traditional clinical-pathologic model and pTNM alone,indicating incremental value for prognosis.Conclusions:CT-based radiomics for primary tumor and reginal lymph nodes was sufficient in predicting OS for patients with ESCC.The integrated model demonstrated incremental value for prognosis and was robust for clinical applications.

CUL4 E3 ligase regulates the proliferation and apoptosis of lung squamous cell carcinoma and small cell lung carcinoma

Objective:The E3 ligase,CRL4,plays diverse roles in different cellular processes,such as DNA damage,transcriptional regulation,cell cycle progression,and cell apoptosis.Our previous study showed that CUL4A and CUL4B had a strong association with tobacco smoking risk in lung squamous cell carcinoma(SCC)and small cell lung carcinoma(SCLC).This study aimed to define the potential mechanism underlying the roles of CUL4A and CUL4B in the development of SCC and SCLC.Methods:We determined the role of CUL4A and CUL4B in the cell cycle and apoptosis of SCC and SCLC,and identified the key apoptosis-related gene involved in the oncogenic activity of CUL4B by Western blot,immunohistochemical staining,flow cytometry,and enzyme inhibition experiments.Results:We found that depletion of CUL4A and CUL4B reduced the proliferation of SCC and SCLC cells.cUL4Aknockdown but not CUL4Bknockdown arrested cells in Gl phase while upregulating P21 and cU L4Bknockdown promoted cell apoptosis through upregulation o f FOXO3A.Accordingly,CUL4B decreased FO X03A expression by activating the ERK signaling pathway and mediating FOXO3A degradation via the ubiquitin-proteasome pathway.Conclusions:These results identified the function of E3 ligase CRL4 in regulating SCC and SCLC cell proliferation,which provides a potential strategy for cancer therapy by targeting FOXO3A and the E3 ligase,CRL4.

CLINICAL SIGNIFICANCES OF THE EXPRESSION OF METALLO- THIONEIN IN FIVE TYPES EPITHELIUM CELL CANCER

Objective： To study the expressions of （CSC）, bladder transitional cell cancer metallothionein and the significances in cervical squamous cell cancer （BTC）, esophageal squamous cell cancer （ESC）, gastral tubular adenocarcinoma （GC） and large intestinal tubular adenocarcinoma （LIC）. Methods： lmmunohistochemical method was used to examine the expression rates of MT in five types of cancer tissue. Results： The expression rates of MT were 75.00% （24/32） in ESC, 52.27% （46/88） in GTC, 59.46% （44/74） in LIC, 64.86% （48/74） in BTC and 58.57% （41/70） in CSC respectively. The positive rates of MT expression were higher in low differentiation and deep muscular group than those in medium or high differentiation and superficial muscular invasion group （P〈0.05）. Conclusion： The expression of MT is related to differentiation degree and invasion degree.

Immunotherapy – new perspective in lung cancer

Lung carcinoma is associated with a high mortality worldwide,being the leading cause of cancer death.It is mainly classified into squamous non-small cell lung cancer(NSCLC),non-squamous NSCLC,and small cell lung cancer.However,such malignancy has been increasingly subdivided into histological and molecular subtypes to guide treatment.Therapies can be used in adjuvant and palliative settings.Regarding immunotherapy,it has been widely tested in both first or subsequent palliative lines.In this sense,drugs such as pembrolizumab,nivolumab,atezolizumab,ipilimumab,avelumab,and durvalumab have been assessed in large studies.Some of these trials have also studied these medicines in adjuvant and in maintenance therapy.In recent years,advances in immunotherapy have raised the hope that the unfavorable prognosis observed in several affected individuals can be changed.Immunotherapy has increased the overall survival in squamous NSCLC,non-squamous NSCLC,and small cell lung cancer.However,it has added to the oncology practice some side effects that are unusual in standard chemotherapy and require special clinical support.In order to show how immunotherapy is being applied in the treatment of lung carcinoma,we reviewed the main studies in adjuvant and palliative scenarios.What is the better scheme?What is the better combination?What is the better dose?When should we use immunotherapy?Does programmed cell death ligand 1 expression significantly interfere in immunotherapy efficiency?Some of these questions have already been answered,while others require more investigations.

Coexistence of tuberculosis and squamous cell carcinoma in the right main bronchus:A case report

BACKGROUND Lung cancer with pulmonary tuberculosis(TB)refers to the occurrence of lesions simultaneously or sequentially in the lung(s)of the same patient,and the pathological examination and sputum TB examination diagnose them as lung cancer and TB,respectively.The occurrence of endobronchial TB(EBTB)with endobronchial tumor sequentially in the same bronchus lesion of the same patient is relatively rare.CASE SUMMARY A 62-year-old female patient was admitted to a local hospital on June 18,2019 after a 3-mo history of dyspnea.She was a farmer and had no history of smoking and alcohol misuse.The patient had neither family nor work contact indicating exposure to TB.Emergency chest computed tomography(CT)examination showed that the right main bronchus was occupied and malignant tumor was possible.Histopathologic examination of a bronchial biopsy showed granulomatous inflammation with caseification and the presence of acid fast bacilli(AFB).However,after 6 mo of antitubercular treatment,repeat bronchoscopy and biopsy histological examination showed squamous cell carcinoma.The patient has started on systemic chemotherapy with carboplatin.After another two cycles of therapy,chest CT showed complete resolution of the lesions.Bronchoalveolar lavage and bronchial aspirate were negative for AFB and cancer cells.CONCLUSION It is not only more likely that a patient presenting with what appears to be TB will concurrently have a pulmonary malignancy than someone who does not have a TB infection,but also that it is of greater urgency to make an expedited diagnosis of the malignancy.

Adenocarcinoma transformed into squamous cell carcinoma in non-small cell lung cancer

Non-small cell lung cancer(NSCLC)is the most common form of lung cancer which remains the deadliest malignancy worldwide(Siegel et al.,2019).In general,NSCLC can be divided into several subtypes,including adenocarcinoma(ADC),squamous cell carcinoma(SCC),adeno-squamous cell carcinoma(AD-SCC)and large cell carcinoma(LCC).

Acute myocardial infarction mimicking squamous cell lung cancer with bone metastases due to hypercalcemia： a case report

Acute myocardial infarction （AMI）, the most severe .coronary artery disease, is one of the most frequent cardiac emergencies, and early diagnosis and treatment are very important to decrease the subsequent cardiac adverse events such as malignant arrhythmia and sudden cardiac death. But in fact, lots of diseases are similar to AMI in clinical practice, of which the most common are myocarditis, pulmonary embolism in department of cardiology. Here we report a case of AMI-like squamous cell lung cancer with bone metastases.

Bowen’s disease with multiple lesions of the penis and scrotum:A case report

Bowen’s disease is a rare squamous cell carcinoma in situ of the skin,the etiology and pathogenesis of which remain unclear.A 57-year-old man presented with the penis and scrotum erythema,with indistinct boundaries with the surrounding tissue.Pathology and histopathology of the biopsy specimen revealed Bowen’s disease.There are many clinical treatments for Bowen’s disease,including surgical excision,liquid nitrogen freezing,electrocautery,laser therapy,topical application of 5-fluorouracil ointment,and photodynamic therapy.Bowen’s disease mostly involves solitary lesions.This case involved multiple lesions,and its scope was extensive;therefore,surgical resection was performed.

Artificial intelligence in endoscopy:The challenges and future directions

Artificial intelligence based approaches,in particular deep learning,have achieved state-of-the-art performance in medical fields with increasing number of software systems being approved by both Europe and United States.This paper reviews their applications to early detection of oesophageal cancers with a focus on their advantages and pitfalls.The paper concludes with future recommendations towards the development of a real-time,clinical implementable,interpretable and robust diagnosis support systems.

RASSF6-TRIM16 axis promotes cell proliferation,migration and invasion in esophageal squamous cell carcinoma

Ras-association(RA) domain family number 6(RASSF6) is a member of the Ras-association domain protein family.It is epigenetically inactive and negatively regulates the malignant progression of some tumors.However,its precise role in esophageal squamous cell carcinoma(ESCC) has not been reported.In this study,we performed immunohistochemistry(IHC) assay.The results show that RASSF6 is upregulated in ESCC and that the elevated expression level of RASSF6 is associated with lymph node metastasis and poor survival of ESCC patients.Consistent with the clinical obse rvations,the upregulation of RASSF6 greatly promotes ESCC cell proliferation,migration and invasion as well as the cell cycle transition to Gl/S phase in vitro.According to models in vivo,the downregulation of RASSF6 considerably inhibits ESCC tumor growth and lung metastasis.Mechanistically,RASSF6 negatively regulates the tumor suppressor tripartite-motif-containing protein 16(TRIM16) by promoting its ubiquitination-dependent degradation and eventually activates pathways associated with the cell cycle and epithelialmesenchymal transition(EMT).Together,these results indicate that the RASSF6-TRIM16 axis is a key effector in ESCC progression and that RASSF6 serves as a potential target for the treatment of ESCC.