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ABSTRACT: ObjectiveImpaired signal transduction is associated with tumorigenesis and progression of various kinds of human cancers. Transforming
growth factor (TGF)-beta/Smad and ras-mitogen activated protein kinase (MAPK) are two major signal transduction pathways for
adjusting cell proliferation and differentiation. Little is known about TGF-beta/Smad4 in non-small cell lung cancer (NSCLC).
Hereby, we investigated the expression of Smad4 in NSCLC, its correlation with MAPK proteins (including p38, ERK1 and JNK1
proteins) and their clinical significance in NSCLC.
MethodsThe expressions of Smad4, p38, ERK1 and JNK1 were detected at protein level with Western blotting and immunohistochemistry,
at transcription level with RT-PCR. Statistical analysis was performed for the comparisons of expressions of Smad4, p38, ERK1
and JNK1, and their correlation with various clinicopathological parameters and the prognosis of NSCLC.
ResultsThe levels of protein and mRNA expression of Smad4 in lung cancer tissues were significantly lower than in normal tissues
(P<0.05). All these four proteins were associated with TNM staging. There was a strongly negative correlation between p38 and
Smad4. Expressions of Smad4, p38 and JNK1, as well as tumor differentiation and staging were significantly correlated with
the prognosis of NSCLC by univariate analysis. By multivariate analysis, only Smad4, p38, tumor differentiation and staging
were correlated with the prognosis. Taken together, the negative expression of p38 and positive expression of Smad4 were associated
with a better prognosis of NSCLC.
ConclusionSmad4 could be of vital importance for the initiation and development of NSCLC. The expression of Smad4 might be inhibited
by p38, supporting a cross-talk between main proteins of TGF-beta/Smad and ras-MAPK signal transduction pathways. Smad4 and
p38 could be possible prognostic factors for NSCLC.
Chinese Journal of Cancer Research 05/2012; 19(4):269-276. · 0.18 Impact Factor
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ABSTRACT: ObjectiveTo investigate the clinical features of pulmonary thromboembolism in patients with primary lung cancer in relation to thoractomy,
and to shed light on prevention, diagnosis and treatment of this fatal disease after lung resection.
MethodsA total of 1245 cases with primary lung cancer received thoracotomy in the past 13 years were retrospectively reviewed. Clinical
data of a total of 14 patients (1.1%) suffering from pulmonary thromboembolism and requiring cardiao-pulmonary resuscitation
were collected and analyzed.
ResultsThe diagnosis was established primarily by clinical findings in 9 cases (64.3%), including further confirmation of one case
during operation, by pulmonary ventilation-perfusion scan in 2, by spiral CT angiography in 1, by pulmonary angiography in
1, and by autopsy in 1 case. Even using prompt resuscitation, 8 patients (57.1%) died within 48 h (mean 4 h) after the onset
of the symptoms. Six cases eventually recovered. Of the 6 salvaged patients, they all received anticoagulation therapy with
heparin intravenously and warfarin orally, including 3 cases of additional thrombolytic therapy with urokinase. Two cases
with massive pulmonary emboli received emergency surgery, including one pulmonary embolectomy, and one bilobectomy after right
upper lobectomy, with satisfactory results.
ConclusionMassive pulmonary embolism is an infrequent but fatal early postoperative complication after lung resection. The diagnosis
should be based mainly on clinical findings in order to initiate the appropriate therapy immediately. The direct diagnostic
techniques including radionuclide pulmonary scan, spiral CT angiography, and pulmonary angiography could be based on a careful
evaluation of the expected benefits and risks of the various available treatments.
Chinese Journal of Cancer Research 04/2012; 18(3):235-240. · 0.18 Impact Factor
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ABSTRACT: ObjectiveTo evaluate the efficacy of ifosfamide and etoposide (VP-16) in patients with small cell lung cancer (SCLC), and investigate
the correlation between microvessel count (MVC) in tumor and chemotherapeutic sensitivity.
MethodsForty-one consecutive cases of SCLC received chemotherapy of ifosfamide plus VP-16, and underwent investigation retrospectively.
Immunohistochemistry using anti-human blood type H monoclonal antibody was conducted and MVC was recorded under light microscope.
ResultsThere were 27 limited-disease and 14 extensive-disease patients. The overall response rate was 92.7% (38/41) with 28 cases
(68.3%) of complete response (CR), 10 (24.4%) with partial response (PR), 3 (7.3%) with progressive disease (PD). The 1-,
2-, 3-, and 5-year survival rates were 68.3% (28/41), 48.3% (20/41), 23.7% (9/38) and 11.1% (3/27), respectively, with the
median survival of 26.8 months. The principal toxicities were grade 3–4 neutropenia in 8 cases (19.5%), grade 3–4 thrombocytopenia
in 6 cases (14.6%), mild liver toxicity in 7 cases (17.0%) and mild renal function damage in 4 cases (9.8%). The mesenchymal
vasculature was clearly visualized, with the mean value of 34.7 under each high microscopic power field. Of SCLC with more
MVC (n=26), CR accounted for 84.6%; while in cancers with less MVC (n=15), CR took up 40.0%, with significant difference (P<0.05).
ConclusionAdministrating ifosfamide and VP-16 is in accordance with the biological features of SCLC and results in beneficial results
as well as acceptable side effects. The MVC is positively correlated with the chemotherapeutic sensitivity, and serves as
a vital factor contributing to chemosensitivity.
Chinese Journal of Cancer Research 04/2012; 18(2):116-120. · 0.18 Impact Factor
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ABSTRACT: To investigate the mechanism underlying bronchiolitis obliterans (OB) following lung transplantation and the significance of transforming growth factor (TGF)-beta1/Smad3 signal pathway in this pathological process.
The tracheas of BALB/c mice were transplanted into the subcutaneous tissues of a Smad3ex8/ex8 gene knock-out Swiss black mouse and a Smad3 wild-type Swiss black mouse. Forty-two days later the tracheas were taken out. Immunocytochemistry was used to detect the alpha-smooth muscle actin (alphaSMA), a marker of fibroblast-myofibroblast differentiation. The tracheas of Smad3 knock-out and wild type mice were taken out, broken to pieces, and cultured to obtain the fibroblasts. The tracheal fibroblasts in primary culture were treated with TGF-beta1. The activation of Smad3 molecules was investigated with immunocytochemistry, Western blotting and DNA electrophoresis mobility gel shift assay (EMSA). Immunocytochemistry staining was also employed to detect the cytoskeletal polymerization and alphaSMA immunofluorescence after incubation with TGF-beta1; Western blotting and RT-PCR was conducted to detect the difference of alphaSMA at transcriptional and protein level.
The number of alphaSMA positive myofibroblasts was great in the experimental OB models produced be transplantation of heterogeneous trachea from Smad3 wild type mice and was very small in the OB model produced be transplantation of heterogeneous trachea from Smad3 knock-out mice (t = 2.125, P = 0.040). Western blotting showed that in vitro experiment showed that phosphorylation of Smad3 protein was increased in the fibroblasts treated with TGF-beta1 and was almost absent in those not treated with TGF-beta1. EMSA showed that DNA binding was increased in the fibroblasts treated with TGF-beta1 and was almost absent in those not treated with TGF-beta1. Immunofluorescence staining showed that the cytoplasm of the fibroblasts not treated with TGF-beta1 was Smad3 positive, however, the nuclei of the fibroblasts treated with TGF-beta1 was Smad3 positive. RT-PCR showed that the alphaSMA mRNA expression level in the Smad3 wild-type fibroblasts was increased after treated with TGF-beta1, and was significantly higher than in the Smad3 knock-out fibroblasts treated with TGF-beta1 (t = 2.080, P = 0.027). Western blotting showed that the alphaSMA protein expression level in the Smad3 wild-type fibroblasts was increased after treatment with TGF-beta1, and was significantly higher than that of the Smad3 knock-out fibroblasts (t = 1.982, P = 0.032).
TGFbeta1 promotes the production of alphaSMA protein and transformation of fibroblasts into myofibroblasts through the Smad3 dependent signal pathway, thus resulting in the development of bronchiolitis obliterans.
Zhonghua yi xue za zhi 09/2007; 87(29):2069-73.
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Hong-xu Liu,
Si-wen Wang,
Cheng-hai Zhao,
Yang Liu, Yu Li,
Qi-gang Zhang,
Wei Cong,
Xin-gang Lan,
Shun Xu,
Li-bo Han,
Lin Zhang
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ABSTRACT: To investigate the mechanism underlying myofibroblast differentiation induced by transforming growth factor (TGF) beta1 in obliterative bronchiolitis following lung transplantation.
Heterotopic tracheal transplantation was performed in Smad3 wild-type and knock-out mice to simulate the lung transplantation in human. Murine tracheal fibroblasts cultivated in primary culture were used for in vitro study. Immunohistochemistry, immunocytochemistry, Western Blotting, RT-PCR and DNA electrophoresis mobility gel shift assay were conducted to detect the expression of alpha-smooth muscle actin (alphaSMA), the marker of fibroblast-myofibroblast differentiation, and the activation of Smad3, p38 and ERK1/2.
In affected airways of experimental obliterative bronchiolitis, abundant expression of alphaSMA were found. In vitro study for tracheal fibroblasts, the activation of Smad3 by TGF-beta1 presents as three major forms, phosphorylation, nuclear translocation and DNA binding. In Smad3 wild-type fibroblasts, TGF-beta1 induces the increase of the myofibroblasts transformation, characterized by the elevation of alphaSMA, both at transcription and protein level. While in Smad3 knock-out fibroblasts, the transformation of myofibroblasts induced by TGF-beta1 is significantly decreased (t = 2.080, P = 0.027; t = 1.982, P = 0.032), but not completely abolished. Further study in Smad3-deficient fibroblasts demonstrates that p38 and ERK1/2 could be activated by TGF-beta1 and result in fibroblast differentiation.
TGF-beta1 could promote the transformation of fibroblasts into myofibroblasts in Smad3 dependent and independent signal pathways, especially the Smad3 dependent path, and result in the development of obliterative bronchiolitis.
Zhonghua wai ke za zhi [Chinese journal of surgery] 08/2007; 45(14):986-9.
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ABSTRACT: To investigate the expression of Smad4 in non-small cell lung cancer (NSCLC), its correlation with MAPK (mitogen activated protein kinase) and their clinical significance in NSCLC.
Western blotting and RT-PCR were employed to test 42 resected lung cancers and normal lung tissues for the expression of Smad4. Imunohistochemistry was used to detect Smad4 and subtribes of MAPK in 71 paraffin samples.
The level of protein and mRNA expression of Smad4 in lung cancer tissues were 0.2092 +/- 0.1308 and 0.3986 +/- 0. 1982, respectively, lower than those in normal tissues (0.7852 +/- 0.4386 and 1.1206 +/- 0.6772, P < 0.05). The expression of p38, ERK1 and Smad4 was associated with TNM staging (P = 0.000, 0.000 and 0.005, respectively) and JNK1 with tumor location (P = 0.028) and staging (P = 0.000). There was a correlation between p38 and Smad4 (P = 0.000). The expression of Smad4 (P = 0.0001), p38 (P = 0.0000) and JNK1 (P = 0.0208), tumor differentiation (P = 0.0059) and staging (P = 0.0000) were significantly correlated with prognosis of NSCLC by univariate analysis. Smad4 (P = 0.019), p38 (P = 0.044), tumor differentiation (P = 0.003), and staging (P = 0.020) were correlated with prognosis tested by multivariable analysis. Taking p38 and Smad4 together, we found that the negative expression of p38 and positive expression of Smad4 were associated with a better prognosis of NSCLC (P = 0.000).
Smad4 could be of importance for the initiation and development of NSCLC. There is a significant correlation between main proteins of TGF-beta/smad4 and those of ras-MAPK signal transduction pathways. The expression of Smad4 is inhibited by p38. Smad4, as well as p38, tumor differentiation and staging can be used as prognostic factors of NSCLC.
Zhonghua zhong liu za zhi [Chinese journal of oncology] 11/2006; 28(10):741-5.
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ABSTRACT: To shed light on the possible role of mismatch repair gene Mlh3 in familial esophageal cancer (FEC).
A total of 66 members from 10 families suggestive of a genetic predisposition to hereditary esophageal cancer were screened for germline mutations in Mlh3 with denaturing high performance liquid chromatography (DHPLC), a newly developed method of comparative sequencing based on heteroduplex detection. For all samples exhibiting abnormal DHPLC profiles, sequence changes were evaluated by cycle sequencing. For any mutation in family members, we conducted a segregation study to compare its prevalence in sporadic esophageal cancer patients and normal controls.
Exons of Mlh3 in all samples were successfully examined. Overall, 4 missense mutations and 3 polymorphisms were identified in 4 families. Mlh3 missense mutations in families 9 and 10 might be pathogenic, but had a reduced penetrance. While in families 1 and 7, there was no sufficient evidence supporting the monogenic explanations of esophageal cancers in families. The mutations were found in 33% of high-risk families and 50% of low-risk families.
Mlh3 is a high risk gene with a reduced penetrance in some families. However, it acts as a low risk gene for esophageal cancer in most families. Mutations of Mlh3 may work together with other genes in an accumulated manner and result in an increased risk of esophageal tumor. DHPLC is a robust and sensitive technique for screening gene mutations.
World Journal of Gastroenterology 10/2006; 12(33):5281-6. · 2.47 Impact Factor
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ABSTRACT: To investigate the relationship between the clinical features and prognosis in young patients with lung cancer who underwent resection.
Statistical analysis was employed on sex, age, symptoms, diagnosis, treatment and prognosis, in 92 young cases younger than 40 years old among 930 cases with primary lung cancer who underwent surgery from January 1978 to December 1996.
There were 92 young patients with lung cancer, accounting for 9.89% of the total cases. They were 71 male and 21 female patients, with the ratio of 3.38:1. The histological types were 34 squamous cell carcinomas (37%), 30 adenocarcinomas (33%), 26 small cell carcinomas (28%), and two large cell carcinomas (2%). On TNM staging, there were 30 cases in stage I (32.6%), 30 in stage II (32.6%) and 32 in stage III (34.8%). Lobectomy was conducted in 54 patients (59%), pneumonectomy in 36 (39%) and wedge-shaped resection in two cases (2%). The rate of pneumonectomy in young patients was significantly higher than that of 18% in older patients (>40) with lung cancer (P<0.01). 57 patients (62%) received absolutely curative resection; 28 cases (30%), relatively curative resection; seven cases (8%), non-curative resection. The postoperative 5-year-survival was 46% (42/92), in comparison with 34% (288/838) in patients older than 40 receiving operation during the same period, with significant difference between the two groups (P<0.05). The 5-year-survivals in patients with squamous cell carcinoma, adenocarcinoma, small cell carcinoma and large cell carcinoma were 68% (23/34), 30% (9/30), 38% (10/26) and 0 (0/2), respectively. The survival in squamous cell cancer was markedly higher than in adenocarcinoma (P<0.01) and in small cell carcinoma (P<0.05). There was no significant difference between adenocarcinoma and small cell cancer. The 5-year-survivals in stage I, II and III were 63% (19/30), 53% (16/30) and 22% (7/32), respectively. There was no significant difference between stage I and II, while remarkable difference was found between stage I and III (P<0.01), and between stage II and III (P<0.05). The 5-year-survival in patients undergoing absolutely curative resection was 67% (38/57), and 14% (4/28) in patients with relatively curative resection, with significant difference (P<0.01). No patient survived longer than the 5th postoperative year in seven cases receiving non-curative resection.
Young patients with lung cancer were more often seen in male than in female. Squamous cell carcinoma accounted for the most part, no statistical difference, however, compared with adenocarcinoma and small cell carcinoma. The pneumonectomy rate in young patients was remarkably higher than that in patients older than 40. The postoperative 5-year-survival in young patients was considerably higher than in patients older than 40 who underwent surgery during the same period. Favorable prognosis was seen in patients with squamous cell carcinoma and undergoing absolutely curative resection, while worse outcome in stage III cancer.
Lung Cancer 11/2003; 42(2):215-20. · 3.43 Impact Factor
