| Esophageal cancer(EC)is the eighth most common cancer and the sixth leading cause of cancer mortality worldwide.Esophageal squamous-cell carcinoma(ESCC)and esophageal adenocarcinoma(EA)are the two major histological subtypes of EC.Despite the incidence has been decreased within recent decades in some places such as North America and Europe,ESCC still occupies the vast majority(over 80%)of EC in China.Although remarkable accomplishment has been achieved in cancer diagnostics and therapeutics in the past decades,the prognosis of ESCC remains discouraging with a dismal 5-year survival rate of less than 20%.ESCC-related morbidity and mortality after therapeutic failure is attributable to tumor recurrence and dissemination of metastases.Most ESCC patients are already in locally advanced or metastatic disease at the right time of diagnosis,lacking the opportunity for radical surgery.Besides,the application of radiotherapy and chemotherapy is strongly limited due to the treatment-related side effects.Thus,to tackle ESCC malignancy,figuring out key factors involved in tumorigenesis & progression and identifying novel diagnostic biomarkers & therapeutic targets is paramount.Micro RNAs(mi RNAs),which are a kind of endogenous small non-coding RNAs with a total length of about 19–25 nucleotides,exert a wide range of biological functions in different cellular processes,including proliferation,differentiation,metabolism and apoptosis in the post-transcriptional level by inhibiting translation of target m RNAs or stimulating m RNA degradation directly via binding the 3’untranslated region(UTR)of target gene.It is believed that more than 30% of human genes are regulated by mi RNAs,the abnormal expression of which have been implicated in the formation and development of numerous tumors.Many studies have found that various mi RNAs dyregulated in esophageal cancer,among which mir-25,mir-424 and mir-151 were increased,while mir-100,mir-99 a,mir-29 c and mir-140 were decreased.Besides,mi RNAs dyregulation was associated with tumor volume,degree of differentiation,tumor invasion and lymph node metastasis.Micro RNA 370(mi R-370)is located within the DLK1/DIO3 imprinting region on human chromosome 14,which has been identified as a cancer-associated genomic region.Substantial evidence demonstrates that mi R-370 serves as a tumor suppressor in malignant cholangiocytes,leukemia cells and oral squamous carcinoma cells In contrast,several studies have reported that overexpression of mi R-370 contributes to the progression of gastric carcinoma,prostate cancer,and acute myeloid leukemia.Nevertheless,the role of mi R-370 in malignances remains controversial.PIN 1(Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1),an evolutionarily conserved member of the peptidylprolyl isomerase(PPIase)family,is the sole that specifically recognizes phosphorylated ser/thr-pro moieties to catalytically regulate the post-phosphorylation conformation of its substrates,resulting in a profound impact on key proteins involved in the regulation of cell proliferation,differentiation and apoptosis.Such unique substrate specificity is conferred by an N-terminal WW domain binding specific phospho-Ser/Thr-Pro modules and a C-terminal PPIase domain catalyzing their cis-trans isomerization.PIN 1,which is upregulated in a variety of cancers,is required for boosting oncogenic signals and blocks proteins with tumor suppressor functions.PIN 1 binds to cyclin D1 phosphorylated at Thr286-Pro by GSK3β and increases cyclin D1 levels in the nucleus and stabilizes cyclin D1.PIN1 binds to the phosphorylated Ser246-Pro motif of β-catenin,which increasesβ-catenin’s stability and its translocation into the nucleus.PIN 1 increases the transcription of β-catenin target genes,thereby enhancing cyclin D1 expression.According to previous publications and the predication of online software,PIN 1 can be regulated by a variety of mi RNAs,including mi R-370.However,the relationship between PIN 1 and mi R-370,as well as the roles of PIN 1 and mi R-370 in the initiation and development of ESCC is poorly understood.Main results:1.Expression of mi R-370 is decreased in ESCC1.1 Mi R-370 is significantly downregulated in ESCC tissues.1.2 In both TE-1 and Eca109 cells,mi R-370 expression is significantly decreased1.3 Lower mi R-370 expression significantly correlated with tumor diameter,poor differentiationand tumor invasionas well as lymph node metastasis1.4 Overexpression of mi R-370 can induce decreased cell proliferation and increased apoptosis in both TE-1 and Eca109 cells1.5 Mi R-370 suppressed ESCC cell growth in vivo2.PIN 1 is overexpression in ESCC2.1 In ESCC tissues,PIN 1 expression is significantly upregulated2.2 In both TE-1 and Eca109 cells,PIN 1 expression is significantly increased2.3 Higher PIN 1 expression significantly correlated with tumor diameter,poor differentiationand tumor invasionas well as lymph node metastasis3.Mechanism of mi R-370/PIN 1 axis involves in ESCC3.1 Co-transfection of PIN 1 can reversed the effects of overexpression mi R-370 on cell proliferation and apoptosis in both TE-1 and Eca109 cells3.2 Concomitant expression of PIN 1 abrogated the inhibition of subcutaneous tumor growth by mi R-3703.3 Mi R-370 can significantly reduce β-catenin and cyclin D1 levels in both ESCC cells,which can also be prevented by co-transfection of PIN 13.4 Mi R-370 can significantly induce Bax,cleaved-caspase-3,cleaved-caspase-9levels in both ESCC cells,which can also be prevented by co-transfection of PIN 1Conclusion:In conclusion,our study identified mi R-370,which directly targets PIN1 m RNA,is significantly down-regulated in both human ESCC tissues and cells.Overexpression of mi R-370 can suppress ESCC cell proliferation in both in and ex vitro experiments.All these changes induced by mi R-370 can be effectively reversed by the co-transfection of PIN 1.These results indicate that mi R-370 acts as a potential tumor suppressor in the initiation and progression of ESCC,which deserves further investigation for clinical application. |
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