| Esophageal carcinoma is a malignant disease with the seventh incidence and sixth leading cause of cancer-related mortality worldwide,and is one of the major health killers of all mankind.In China,esophageal squamous cell carcinoma is the main type of esophageal carcinoma,accounting for 90%of all patients.Usually,surgical strategy is chosen to treat early stage tumors which can often achieve satisfactory results.However,due to the insignificant symptoms of early esophageal squamous cell carcinoma,most patients are already in locally advanced stages when they seek help.Neoadjuvant therapy combined with surgery is the preferred treatment for locally advanced esophageal squamous cell carcinoma.Although neoadjuvant therapy brings new hope to these patients,drug resistance will inevitably occur,so it is particularly important to explore the development and drug resistance mechanism of esophageal squamous cell carcinoma.The fibroblast growth factor(FGF)family can regulate various developmental processes in the body and has been shown to play a key role in the occurrence and development of various tumors.As an important member of FGFs,the role of FGF19 on tumorigenesis and development is also increasing recently.Studies have shown that FGF 19 can promote the occurrence and development of various tumors such as liver cancer,prostate cancer,breast cancer,thyroid cancer and lung cancer.FGF19 is a relatively clear tumor-promoting factor,but its role on the mechanism of esophageal squamous cell carcinoma development is still unclear due to limited studies.This part of our study aims to explore the role of FGF 19 on the occurrence,development and neoadjuvant chemotherapy resistance of esophageal squamous cell carcinoma and its related mechanisms.Firstly,we conducted a pan-cancer analysis and found that FGF19 was highly expressed in a variety of tumors and correlated with their poor prognosis.Secondly,we analyzed the expression level of FGF 19 in esophageal squamous cell carcinoma,through analyzing the data in TCGA and GEO databases.We found that FGF 19 gene was abnormally highly expressed in esophageal squamous cell carcinoma and was associated with its poor prognosis.Thirdly,in the sequencing data of 155 patients with esophageal squamous cell carcinoma who received surgical treatment in our hospital,the mRNA expression of FGF19 was significantly increased in esophageal squamous cell carcinoma tissues compared with adjacent tissues.By analyzing the information of 103 cases of tissue microarray and 72 cases of esophageal squamous cell carcinoma patients in our hospital,the results showed that the expression of FGF19 in esophageal squamous cell carcinoma was significantly correlated with lymph node metastasis and TNM stage,and the high expression of FGF19 protein may be an independent risk factor for the prognosis of patients with esophageal squamous cell carcinoma.In addition,we found that in all patients with esophageal squamous cell carcinoma who received neoadjuvant chemotherapy,the expression level of FGF19 in patients with response PD/SD was significantly higher than that with response CR/PR,and the difference was statistically significant.And high expression of FGF19 is significantly associated with poor prognosis in patients with esophageal squamous cell carcinoma receiving neoadjuvant chemotherapy.Fourthly,the biological functions of FGF19 in ESCC cells was studied,the results showed that overexpression of FGF19 can promote the proliferation,migration,invasion,anti-apoptosis,tumorigenesis and chemoresistance ability of esophageal squamous cell carcinoma.Finally,we investigated the role of FGF19 on the mechanism of esophageal squamous cell carcinoma development.Usually,FGF19 interacts with FGFR4 to regulate downstream signaling pathways to participate in the occurrence and development of tumors.Our results showed that the mechanism that PI3K/AKT signaling pathway participate in the process of FGF19-FGFR4 regulating the biological function of esophageal squamous cell carcinoma.Taken together,FGF19 may be a novel prognostic marker and oncogene for multiple tumors.We further explored the role of FGF19 in esophageal squamous cell carcinoma,and found that FGF19 is bighly expressed in esophageal squamous cell carcinoma and is related to chemotherapy resistance and poor prognosis.In vivo and in vitro experiments showed that overexpression of FGF19 can promote the proliferation,migration,invasion,anti-apoptosis,tumorigenesis and chemoresistance ability of esophageal squamous cell carcinoma.And the regulation process may be achieved by activating the PI3K/AKT signaling pathway.Esophageal squamous cell carcinoma(ESCC)is considered a highly malignant tumor and prone to lymph node metastasis(LNM).The presence of LNM is associated with the poor prognosis of patients with thoracic ESCC.Currently,the standard treatment strategy for resectable ESCC involves esophagectomy combined with systematic lymphadenectomy.The left tracheobronchial lymph node(4L)is considered regional lymph node(LN)for thoracic ESCC,but routine prophylactic 4L LN dissection performed for all resectable ESCC is still under debate.Station 4L LN dissection is more technically challenging and time-consuming than other lymph node stations because of anatomic limitations.They are located deeply within the subaortic region close to the left recurrent laryngeal nerve,aortic arch,left pulmonary artery and left main bronchial membrane.Currently,few studies reported the clinical significance of 4L LN dissection and station 4L LNM in patients with ESCC.Thus,we carried out this study to evaluate the effect of 4L LN dissection and station 4L LNM on the survival of patient with ESCC,and analyze the risk factors of station 4L LNM.From January 2010 to December 2018,3522 patients with EC who underwent radical esophagectomy combined with lymphadenectomy were collected from the retrospective institutional database.Clinical characteristics,including age,sex,smoking index,alcohol abuse,degree of differentiation,tumor length,tumor location,clinical T stage and N stage,were analyzed.Categorical variables were presented as absolute number and percentage,and Chi-square or Fisher’s exact tests were conducted to compare patient characteristics.The balance of variables between two groups were evaluated by calculating the standardized differences(SD),and a value<0.10 was considered as criteria of sufficient balance.The primary end point was overall survival(OS).Survival curves were estimated by a Kaplan-Meier method and log-rank test was conducted to compare differences.Multivariate Cox survival analysis was used to identify independent risk factors for prognosis.Moreover,the propensity score matching(PSM)method was then performed to balance patient characteristics between two groups.Finally,univariable and multivariable logistic regression analysis were performed to evaluate the relation between risk factors and station 4L LNM.In the whole cohort,608(17.3%)patients underwent station 4L LN dissection Of patients underwent 4L LN dissection,45 patients had 4L LNM(7.4%).We carried out this study to evaluate the effect of 4L LN dissection and station 4L LNM on the survival of patient with ESCC.The 5-year OS rates were 69.3%in patients with station 4L LN dissection and 61.7%in patients without,indicating a significant difference(P=0.001).After PSM,patients who received the 4L LN dissection had a superior long-term survival compared with those did not(5-year OS rate:68.2%vs.64.6%,P=0.012).Simultaneously,multivariate Cox survival analysis was performed in the original cohort(3522 patients),and the results showed that station 4L LN dissection was an independent influencing factors for better prognosis(HR:0.850,95%CI:0.725-0.996,P=0.045).In addition,in the patient population who received 4L LN dissection,the OS of patients with station 4LLNM was significantly poorer than those without station 4L LNM(5-year OS rate:45.5%vs.71.1%,P<0.001).After balance in baseline characteristics,the 5-year OS rates were 40.5%in patients with station 4L LNM and 62.2%in patients without,indicating a significant poorer long-term survival in patients with station 4L LNM(P=0.029).Simultaneously,multivariate Cox survival analysis was conducted in all patients who received 4L LN dissection(608 patients),and the results showed that station 4L LNM was an independent risk factors for poorer prognosis(HR:1.932,95%CI:245-2.999,P=0.003).Finally,all patients(608 patients)who underwent station 4L LN dissection were included in subgroup analysis to identify risk factors for 4L LNM.Multivariate logistic analysis revealed that clinical T staging(OR,1.281;95%CI,1.065-2.209;P=0.028)and tumor differentiation(OR,2.495;95%CI,1.326-4.695;P=0.005)were independent risk factors for station 4L LNM.In this study,station 4L LNM was associated with a poorer prognosis of patients with thoracic ESCC,but station 4L LN dissection seems to be associated with a more favorable prognosis.Multivariable analysis showed that clinical T stage and tumor differentiation were independent risk factors for station 4L LNM.For patients with high risk,routine prophylactic 4L LN dissection should be recommend. |
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