ABSTRACT
BACKGROUND@#Small cell lung cancer (SCLC) with high c-Myc expression is prone to relapse and metastasis, leading to extremely low survival rate. Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor Abemaciclib plays a key role in the treatment of tumors, but the effects and mechanisms on SCLC remain unclear. This study was to analyze the effect and molecular mechanism of Abemaciclib in inhibiting proliferation, migration and invasion of SCLC with high c-Myc expression, with a view to expanding a new direction for reducing the recurrence and metastasis.@*METHODS@#Proteins interacting with CDK4/6 were predicted using the STRING database. The expressions of CDK4/6 and c-Myc in 31 cases of SCLC cancer tissues and paired adjacent normal tissues were analyzed by immunohistochemistry. The effects of Abemaciclib on the proliferation, invasion and migration of SCLC were detected by CCK-8, colony formation assay, Transwell and migration assay. Western blot was used to detect the expressions of CDK4/6 and related transcription factors. Flow cytometry was used to analyze the effects of Abemaciclib on the cell cycle and checkpoint of SCLC.@*RESULTS@#The expression of CDK4/6 was associated with c-Myc by STRING protein interaction network. c-Myc can directly modalize achaete-scute complex homolog 1 (ASCL1), neuronal differentiation 1 (NEUROD1) and Yes-associated protein 1 (YAP1). Moreover, CDK4 and c-Myc regulate the expression of programmed cell death ligand 1 (PD-L1). Immunohistochemistry showed that the expressions of CDK4/6 and c-Myc in cancer tissues were higher than those in adjacent tissues(P<0.0001). CCK-8, colony formation assay, Transwell and migration assay verified that Abemaciclib could effectively inhibit the proliferation, invasion and migration of SBC-2 and H446OE(P<0.0001). Western blot analysis further showed that Abemaciclib not only inhibited CDK4 (P<0.05) and CDK6 (P<0.05), but also affected c-Myc (P<0.05), ASCL1 (P<0.05), NEUROD1 (P<0.05) and YAP1 (P<0.05), which are related to SCLC invasion and metastasis. Flow cytometry showed that Abemaciclib not only inhibited the cell cycle progression of SCLC cells (P<0.0001), but also significantly increased PD-L1 expression on SBC-2 (P<0.01) and H446OE (P<0.001).@*CONCLUSIONS@#Abemaciclib significantly inhibits the proliferation, invasion, migration and cell cycle progression of SCLC by inhibiting the expressions of CDK4/6, c-Myc, ASCL1, YAP1 and NEUROD1. Abemaciclib can also increase the expression of PD-L1 in SCLC.
Subject(s)
Humans , Small Cell Lung Carcinoma , B7-H1 Antigen , Sincalide , Lung Neoplasms , Neoplasm Recurrence, Local , Transcription Factors , Adaptor Proteins, Signal Transducing , Cell ProliferationABSTRACT
A 61-year-old male patient was simultaneously diagnosed with lung adenocarcinoma and inflammatory myofibroblastic tumor (IMT). The lung adenocarcinoma and IMT harbored two distinct types of ALK translocation, LOC101927285-ALK, and TPM3-ALK, respectively. The ALK Ventana showed strong positivity on both lesions. The patient was therefore given an endobronchial cryotherapy and ALK inhibitor crizotinib. The tumors showed durable response however the left lung adenocarcinoma relapsed at 17th month post-crizotinib treatment. Tissue re-biopsy on the resistant tumor revealed an ALK exon 23 C1156Y missense mutation in addition to LOC101927285-ALK mutation. Further RNA-based sequence uncovered that the noncoding region rearrangement is the fusion mutation of EML4-ALK. The patient was therefore received alectinib, and the tumor exhibited partly response. Overall, it is very rare that two types of pulmonary tumors exist in one patient driven by two distinct ALK fusions, which emphasizes the necessity of gene sequencing in clinical decision-making and individualized therapy.
ABSTRACT
A 61-year-old male patient was simultaneously diagnosed with lung adenocarcinoma and inflammatory myofibroblastic tumor (IMT). The lung adenocarcinoma and IMT harbored two distinct types of ALK translocation, LOC101927285-ALK, and TPM3-ALK, respectively. The ALK Ventana showed strong positivity on both lesions. The patient was therefore given an endobronchial cryotherapy and ALK inhibitor crizotinib. The tumors showed durable response however the left lung adenocarcinoma relapsed at 17th month post-crizotinib treatment. Tissue re-biopsy on the resistant tumor revealed an ALK exon 23 C1156Y missense mutation in addition to LOC101927285-ALK mutation. Further RNA-based sequence uncovered that the noncoding region rearrangement is the fusion mutation of EML4-ALK. The patient was therefore received alectinib, and the tumor exhibited partly response. Overall, it is very rare that two types of pulmonary tumors exist in one patient driven by two distinct ALK fusions, which emphasizes the necessity of gene sequencing in clinical decision-making and individualized therapy.
ABSTRACT
10.3969/j.issn.1000-8179.2013.12.002
ABSTRACT
Objective: To discuss the clinical features of basaloid squamous carcinoma(BSC)and the factors relating to its prognosis and to compare patient survival between poorly differentiated squamous cell carcinoma(PDSC)and BSC. Methods: Clinical and pathological data of BSC and PDSC cases seen in our hospital between January 2004 and December 2008 were reviewed. Results: There were no statistical differences in demographic and clinical features between PDSC and BSC patients,with the exception that a larger proportion of BSC patients were female(P=-0.001).Additionally,higher tobacco consumption was observed among BSC male patients (P=0.003).There were no significant differences in survival rate between BSC and PDSC groups(X2=0.03,P=0.5470).The median survival time of BSC and PDSC patients was 19 months and 30 months，respectively.The 4-year survival rate was 22.4%and 36.1%，respectively(u=0.740,P=0.230).No significant difference was found in survival rate between stage Ⅰ and stage Ⅱ patients(X~2=0.109，P=0.2974).The median survival time of stage Ⅰ and stage Ⅱ patients was 19 months and 46 months，respectively；and the 4-year survival rate of stage Ⅰ and stage Ⅱ patients was 47.3% and 45.2%，respectively(u=0.122，P=0.450).Using Cox proportional hazard model，we found that surgical types and clinical stages of BSC were correlated with its prognosis.Compared with that of patients who received lobectomy,the postoperative mortality hazard of patients who received pneumonectomy and segmentectomy was increased by 1.379 times(P=0.031)and 1.634 times(P=0.061)，respectively.A more advanced clinical stage was associated with an increase in the postoperative morta,ty hazard ratio(X~2=14.12,P=0.000).The postoperative mortality hazard of patients of stage Ⅲ and stage Ⅳ was 2.437 times higher than that of stage Ⅰ patients(P=0.018).There were no statistical differences in postoperative mortality risk between stage Ⅰ patients and stage Ⅱ patients(P=0.057). Conclusion: Compared with that of PDSC,the incidence of BSC is higher among females.However,there is no difference in the prognosis between BSC and PDSC.BSC can be treated with the same therapies as those for other types of non-small cell lung cancer(NSCLC).