Oral squamous cell carcinoma(OSCC)is the most common head and neck malignancy worldwide,accounting for more than 90%of all oral cancers,and is characterized by high invasiveness and poor long-term prognosis.Its etiolo...Oral squamous cell carcinoma(OSCC)is the most common head and neck malignancy worldwide,accounting for more than 90%of all oral cancers,and is characterized by high invasiveness and poor long-term prognosis.Its etiology is multifactorial,involving tobacco use,alcohol consumption,and human papillomavirus(HPV)infection.Oral leukoplakia and erythroplakia are the main precancerous lesions lesions,with oral leukoplakia being the most common.Both OSCC and premalignant lesions are closely associated with aberrant activation of multiple signaling pathways.Post-translational modifications(such as ubiquitination and deubiquitination)play key roles in regulating these pathways by controlling protein stability and activity.Growing evidence indicates that dysregulated ubiquitination/deubiquitination can mediate OSCC initiation and progression via aberrant activation of signaling pathways.The ubiquitination/deubiquitination process mainly involves E3 ligases(E3s)that catalyze substrate ubiquitination,deubiquitinating enzymes(DUBs)that remove ubiquitin chains,and the 26S proteasome complex that degrades ubiquitinated substrates.Abnormal expression or mutation of E3s and DUBs can lead to altered stability of critical tumorrelated proteins,thereby driving OSCC initiation and progression.Therefore,understanding the aberrantly activated signaling pathways in OSCC and the ubiquitination/deubiquitination mechanisms within these pathways will help elucidate the molecular mechanisms and improve OSCC treatment by targeting relevant components.Here,we summarize four aberrantly activated signaling pathways in OSCC―the PI3K/AKT/mTOR pathway,Wnt/β-catenin pathway,Hippo pathway,and canonical NF-κB pathway―and systematically review the regulatory mechanisms of ubiquitination/deubiquitination within these pathways,along with potential drug targets.PI3K/AKT/mTOR pathway is aberrantly activated in approximately 70%of OSCC cases.It is modulated by E3s(e.g.,FBXW7 and NEDD4)and DUBs(e.g.,USP7 and USP10):FBXW7 and USP10 inhibit signaling,while NEDD4 and USP7 potentiate it.Aberrant activation of the Wnt/β-catenin pathway leads toβ-catenin nuclear translocation and induction of cell proliferation.This pathway is modulated by E3s(e.g.,c-Cbl and RNF43)and DUBs(e.g.,USP9X and USP20):c-Cbl and RNF43 inhibit signaling,while USP9X and USP20 potentiate it.Hippo pathway inactivation permits YAP/TAZ to enter the nucleus and promotes cancer cell metastasis.This pathway is modulated by E3s(e.g.,CRL4^(DCAF1) and SIAH2)and DUBs(e.g.,USP1 and USP21):CRL4^(DCAF1) and SIAH2 inhibit signaling,while USP1 and USP21 potentiate it.Persistent activation of the canonical NF-κB pathway is associated with an inflammatory microenvironment and chemotherapy resistance.This pathway is modulated by E3s(e.g.,TRAF6 and LUBAC)and DUBs(e.g.,A20 and CYLD):A20 and CYLD inhibit signaling,while TRAF6 and LUBAC potentiate it.Targeting these E3s and DUBs provides directions for OSCC drug research.Small-molecule inhibitors such as YCH2823(a USP7 inhibitor),GSK2643943A(a USP20 inhibitor),and HOIPIN-8(a LUBAC inhibitor)have shown promising antitumor activity in preclinical models;PROTAC molecules,by binding to surface sites of target proteins and recruiting E3s,achieve targeted ubiquitination and degradation of proteins insensitive to small-molecule inhibitors,for example,PU7-1-mediated USP7 degradation,offering new strategies to overcome traditional drug limitations.Currently,NX-1607(a Cbl-b inhibitor)has entered phase I clinical trials,with preliminary results confirming its safety and antitumor activity.Future research on aberrant E3s and DUBs in OSCC and the development of highly specific inhibitors will be of great significance for OSCC precision therapy.展开更多
OBJECTIVE To investigate the clinical and functional association of mi R-194 in human laryngeal squamous cell carcinoma(LSCC).METHODS Cell growth was measured by MTT assay.Cel cycle distribution was detected using PI ...OBJECTIVE To investigate the clinical and functional association of mi R-194 in human laryngeal squamous cell carcinoma(LSCC).METHODS Cell growth was measured by MTT assay.Cel cycle distribution was detected using PI staining by flow cytometric analysis.Cell migration and invasion were examined by wound healing assay and transwell assay.The 3′-UTR activity was detected by luciferase assay.The expression level of proteins and mR NA were analysed by Western blotting,immunohistochemistry and q RT-PCR.Mouse xenograft model was established to observe the tumor growth in vivo.RESULTS The expression level of miR-194 is significantly lower in clinical LSCC tissues compared with normal tissues,and is correlated with lymph node metastasis and TNM stage.Kaplan-Meier analysis shows that high miR-194 expression predicts a favorable outcome for LSCC patients.Functional assays show that enforced expression of mi R-194 inhibits the growth,migration,invasion and drug-resistance of LSCC cells.Moreover,Wee1 is identified as a novel functional target of mi R-194.Exogenous expression of Wee1 protein in mi R-194-over expressing cells partially reverses the suppressive effects of mi R-194 on LSCC cells.In addition,Wee1 was abnormally overexpressed in clinical LSCC tissues,and its protein levels were inversely correlated with miR-194 expression.High Wee1 protein level was also associated with TNM stage,lymph node metastasis and poor prognosis.CONCLUSION Our study provides new sights into the role of miR-194/Wee1 axis in LSCC,and suggests a novel miR-194/Wee1-based clinical intervention target for LSCC patients.展开更多
This paper discussed 378 cases of lung cancer which were identified pathologically in the thoracic department of China Medical University from 1980～1986. The sections were stained with H.E., PAS-ab and Keratin, and c...This paper discussed 378 cases of lung cancer which were identified pathologically in the thoracic department of China Medical University from 1980～1986. The sections were stained with H.E., PAS-ab and Keratin, and compared with sections of 131 cases of lung cancer being confirmed beforehand from 1978～1984. Chinese cases showed epidermoid carcinoma 165 (male 146), adenocarcinoma 136(male 82), small cell carcinoma 29 (male 21), large cell carcinoma 19 (male 15) and the others 29 (male 27); Japanese cases were 59(50), 53(25), 3 (2), 11(10), 3(0) respectively. The cases under 40 years of age were 23(6.1%) in China, 3(2.3%)in Japan. Both of them have similar character of histology. But the incidence of lung cancer in youth is higher in China.展开更多
文摘Oral squamous cell carcinoma(OSCC)is the most common head and neck malignancy worldwide,accounting for more than 90%of all oral cancers,and is characterized by high invasiveness and poor long-term prognosis.Its etiology is multifactorial,involving tobacco use,alcohol consumption,and human papillomavirus(HPV)infection.Oral leukoplakia and erythroplakia are the main precancerous lesions lesions,with oral leukoplakia being the most common.Both OSCC and premalignant lesions are closely associated with aberrant activation of multiple signaling pathways.Post-translational modifications(such as ubiquitination and deubiquitination)play key roles in regulating these pathways by controlling protein stability and activity.Growing evidence indicates that dysregulated ubiquitination/deubiquitination can mediate OSCC initiation and progression via aberrant activation of signaling pathways.The ubiquitination/deubiquitination process mainly involves E3 ligases(E3s)that catalyze substrate ubiquitination,deubiquitinating enzymes(DUBs)that remove ubiquitin chains,and the 26S proteasome complex that degrades ubiquitinated substrates.Abnormal expression or mutation of E3s and DUBs can lead to altered stability of critical tumorrelated proteins,thereby driving OSCC initiation and progression.Therefore,understanding the aberrantly activated signaling pathways in OSCC and the ubiquitination/deubiquitination mechanisms within these pathways will help elucidate the molecular mechanisms and improve OSCC treatment by targeting relevant components.Here,we summarize four aberrantly activated signaling pathways in OSCC―the PI3K/AKT/mTOR pathway,Wnt/β-catenin pathway,Hippo pathway,and canonical NF-κB pathway―and systematically review the regulatory mechanisms of ubiquitination/deubiquitination within these pathways,along with potential drug targets.PI3K/AKT/mTOR pathway is aberrantly activated in approximately 70%of OSCC cases.It is modulated by E3s(e.g.,FBXW7 and NEDD4)and DUBs(e.g.,USP7 and USP10):FBXW7 and USP10 inhibit signaling,while NEDD4 and USP7 potentiate it.Aberrant activation of the Wnt/β-catenin pathway leads toβ-catenin nuclear translocation and induction of cell proliferation.This pathway is modulated by E3s(e.g.,c-Cbl and RNF43)and DUBs(e.g.,USP9X and USP20):c-Cbl and RNF43 inhibit signaling,while USP9X and USP20 potentiate it.Hippo pathway inactivation permits YAP/TAZ to enter the nucleus and promotes cancer cell metastasis.This pathway is modulated by E3s(e.g.,CRL4^(DCAF1) and SIAH2)and DUBs(e.g.,USP1 and USP21):CRL4^(DCAF1) and SIAH2 inhibit signaling,while USP1 and USP21 potentiate it.Persistent activation of the canonical NF-κB pathway is associated with an inflammatory microenvironment and chemotherapy resistance.This pathway is modulated by E3s(e.g.,TRAF6 and LUBAC)and DUBs(e.g.,A20 and CYLD):A20 and CYLD inhibit signaling,while TRAF6 and LUBAC potentiate it.Targeting these E3s and DUBs provides directions for OSCC drug research.Small-molecule inhibitors such as YCH2823(a USP7 inhibitor),GSK2643943A(a USP20 inhibitor),and HOIPIN-8(a LUBAC inhibitor)have shown promising antitumor activity in preclinical models;PROTAC molecules,by binding to surface sites of target proteins and recruiting E3s,achieve targeted ubiquitination and degradation of proteins insensitive to small-molecule inhibitors,for example,PU7-1-mediated USP7 degradation,offering new strategies to overcome traditional drug limitations.Currently,NX-1607(a Cbl-b inhibitor)has entered phase I clinical trials,with preliminary results confirming its safety and antitumor activity.Future research on aberrant E3s and DUBs in OSCC and the development of highly specific inhibitors will be of great significance for OSCC precision therapy.
基金The project supported by National Natural Science Foundation of China(31271444,81201726)the Guangdong Natural Science Funds(2015TQ01R350,2014A030313057)the Guangdong Science and Technology Program(2016A050502027,2013B021800088)
文摘OBJECTIVE To investigate the clinical and functional association of mi R-194 in human laryngeal squamous cell carcinoma(LSCC).METHODS Cell growth was measured by MTT assay.Cel cycle distribution was detected using PI staining by flow cytometric analysis.Cell migration and invasion were examined by wound healing assay and transwell assay.The 3′-UTR activity was detected by luciferase assay.The expression level of proteins and mR NA were analysed by Western blotting,immunohistochemistry and q RT-PCR.Mouse xenograft model was established to observe the tumor growth in vivo.RESULTS The expression level of miR-194 is significantly lower in clinical LSCC tissues compared with normal tissues,and is correlated with lymph node metastasis and TNM stage.Kaplan-Meier analysis shows that high miR-194 expression predicts a favorable outcome for LSCC patients.Functional assays show that enforced expression of mi R-194 inhibits the growth,migration,invasion and drug-resistance of LSCC cells.Moreover,Wee1 is identified as a novel functional target of mi R-194.Exogenous expression of Wee1 protein in mi R-194-over expressing cells partially reverses the suppressive effects of mi R-194 on LSCC cells.In addition,Wee1 was abnormally overexpressed in clinical LSCC tissues,and its protein levels were inversely correlated with miR-194 expression.High Wee1 protein level was also associated with TNM stage,lymph node metastasis and poor prognosis.CONCLUSION Our study provides new sights into the role of miR-194/Wee1 axis in LSCC,and suggests a novel miR-194/Wee1-based clinical intervention target for LSCC patients.
文摘This paper discussed 378 cases of lung cancer which were identified pathologically in the thoracic department of China Medical University from 1980～1986. The sections were stained with H.E., PAS-ab and Keratin, and compared with sections of 131 cases of lung cancer being confirmed beforehand from 1978～1984. Chinese cases showed epidermoid carcinoma 165 (male 146), adenocarcinoma 136(male 82), small cell carcinoma 29 (male 21), large cell carcinoma 19 (male 15) and the others 29 (male 27); Japanese cases were 59(50), 53(25), 3 (2), 11(10), 3(0) respectively. The cases under 40 years of age were 23(6.1%) in China, 3(2.3%)in Japan. Both of them have similar character of histology. But the incidence of lung cancer in youth is higher in China.
