TMEM176B Promotes EMT via FGFR/JNK Signalling in Development and Tumourigenesis of Lung Adenocarcinoma.

Lung cancer, the leading cause of cancer-related incidence and mortality worldwide, is characterised by high invasiveness and poor prognosis. Novel therapeutic targets are required, especially for patients with inoperable metastatic disease requiring systemic therapies to improve patients' welfare. Recently, studies indicated that TMEM176B is a positive regulator in breast and gastric cancers, and it could be a potential target for treatment. In this study, we used single-cell sequencing, proteomics, Co-IP, and in vivo and in vitro experimental models to investigate the role of TMEM176B in lung adenocarcinoma development. Our study indicated that TMEM176B expression was enhanced in lung adenocarcinoma tissues, and it was associated with shorter overall survival (OS). TMEM176B promoted cellular functions, including cell proliferation, invasion, migration and adhesion in vitro and tumour growth in vivo. Moreover, the tube formation ability of endothelial cells was enhanced by treating with the tumour cell-conditioned medium. We have also demonstrated that TMEM176B regulated EMT via the FGFR1/JNK/Vimentin/Snail signalling cascade. Overall, our study suggests TMEM176B could be a potential therapeutic target in lung adenocarcinoma.

Emerging trends and research foci of berberine on tumor from 2002 to 2021: A bibliometric article of the literature from WoSCC.

Background: Cancer, also known as a malignant tumor, is caused by the activation of oncogenes, which leads to the uncontrolled proliferation of cells that results in swelling. According to the World Health Organization (WHO), cancer is one of the main causes of death worldwide. The main variables limiting the efficacy of anti-tumor treatments are side effects and drug resistance. The search for natural, safe, low toxicity, and efficient chemical compounds in tumor research is essential. Berberine is a pentacyclic isoquinoline quaternary ammonium alkaloid isolated from Berberis and Coptis that has long been used in clinical settings. Studies in recent years have reported the use of berberine in cancer treatment. In this study, we performed a bibliometric analysis of berberine- and tumor-related research. Materials and methods: Relevant articles from January 1, 2002, to December 31, 2021, were identified from the Web of Science Core Collection (WOSCC) of Clarivate Analytics. Microsoft Excel, CiteSpace, VOSviewer, and an online platform were used for the literary metrology analysis. Results: A total of 1368 publications had unique characteristics. Publications from China were the most common (783 articles), and Y. B. Feng (from China) was the most productive author, with the highest total citations. China Medical University (Taiwan) and Sun Yat-sen University (China) were the two organizations with the largest numbers of publications (36 each). Frontiers in Pharmacology was the most commonly occurring journal (29 articles). The present body of research is focused on the mechanism, molecular docking, and oxidative stress of berberine in tumors. Conclusion: Research on berberine and tumors was thoroughly reviewed using knowledge map and bibliometric methods. The results of this study reveal the dynamic evolution of berberine and tumor research and provide a basis for strategic planning in cancer research.

Methyltransferase-like protein 11A promotes migration of cervical cancer cells via up-regulating ELK3.

Cervical cancer is one of the common malignancies in women, which is characterized with high invasion and metastatic tendency in its advanced stage. Increasing evidence indicates that methyltransferase-like (METTL) gene family is involved in the progression of various cancers. However, the functional role of methyltransferase-like gene family in cervical cancer remains unclear. In the present study, we found that METTL11A, a member of the methyltransferase-like gene family, was significantly over-expressed in cervical carcinoma by analyzing TCGA database. This finding was further validated in clinical tissue samples. Moreover, ectopic expression of METTL11A in cervical cancer cell lines promoted cell proliferation and migration both in vitro and in vivo. Differential gene expression analysis in the transcriptomic sequencing data indicated that ELK3 was down-regulated in METTL11A-silenced cervical cancer cells, which was further verified at both protein and mRNA levels. Functional experiments identified that METTL11A promoted migration of cervical cancer cells in an ELK3-dependent manner. This study will promote understanding the mechanism of cervical cancer progression and the functional role of methyltransferase-like gene families in cancers.

Reduced kinase D­interacting substrate of 220 kDa (Kidins220) in pancreatic cancer promotes EGFR/ERK signalling and disease progression.

Kidins220 is a transmembrane scaffold protein involved in several types of cancer. The aim of the present study was to examine the role of Kidins220 in tumorigenesis and disease progression of pancreatic cancer. The relevant signalling pathways including EGFR, EMT, and MMP were also investigated. The expression of Kidins220 was examined at the transcript and protein level. The Kidins220 knockdown cell model was established and its influence on cellular functions was determined. Involvement of Kidins220 in tumorigenesis and metastasis was examined in CD1 mice, respectively. The results showed that, reduced Kidin220 expression was associated with tumorigenesis, metastasis, and overall survival of pancreatic cancer. Knockdown of Kidins220 promoted proliferation, colony formation and tumorigenic capacity of pancreatic cancer cells in vitro and in vivo, respectively. Kidins220 regulated pancreatic cancer cell migration through the EGFR/AKT/ERK signalling pathway. Furthermore, enhanced EMT was observed in the pancreatic cancer cell lines with the knockdown of Kidins220, underlying EGFR regulation. Kidins220 also affected cell invasion via MMP1. A reduced expression of Kidins220 was observed in pancreatic cancer, which is associated with disease progression, distant metastasis and poor prognosis. The loss of Kidins220 in pancreatic cancer may contribute to disease progression through the upregulation of EGFR and downstream signalling.

Altered expression of striatin-4 is associated with poor prognosis in bladder transitional cell carcinoma.

Striatin-4 (STRN4 or Zinedin) is a scaffolding protein belonging to the mammalian STRN family of proteins and consists of multiple functional signaling domains. Due to its numerous signaling complexes, STRN4 has been reported to be involved in the tumorigenesis of various cancer types, including colon cancer, liver cancer and prostate cancer. However, few studies on STRN4 have been conducted in bladder cancer, and its prognostic role in bladder cancer remains unknown. The present study aimed to investigate the expression levels of STRN4 in bladder transitional cell carcinoma and evaluate the prognostic role of STRN4. STRN4 expression in clinical specimens was analyzed using immunohistochemistry and reverse transcription-quantitative PCR. It was demonstrated that STRN4 expression was significantly associated with clinical parameters such as tumor size, muscle invasion depth and pathological tumor grade. Abnormal STRN4 expression was typically associated with worse overall survival time and outcome when compared with the low STRN4 expression group. Using multivariate analysis, it was reported that STRN4 was an independent prognostic biomarker for survival time in bladder transitional cell carcinoma. Although the specific biological mechanisms of STRN4 in bladder cancer still remain to be elucidated, STRN4 expression could be a prognostic indicator in bladder cancer.

Noggin is associated with a poor prognosis of gastric cancer by promoting the proliferation of gastric cancer cells via the upregulation of EGFR.

Noggin is an antagonist of bone morphogenetic proteins (BMP), being indispensable for certain developmental events. The present study aimed to examine the role of Noggin in the development and prognosis of gastric cancer (GC) and to elucidate the underlying mechanisms. The expression of Noggin in GC was evaluated by RT­qPCR, immunohistochemistry and by the analyses of publicly available databases. The effects of Noggin on proliferation, cell cycle, adhesion, invasion, colony formation and tumour spheroid were examined following both the knockdown and overexpression of Noggin in GC cell lines. The involvement of epidermal growth factor receptor (EGFR) signalling was examined by western blot analysis and by using small molecule inhibitors. As a result, a higher expression of Noggin in GC was found to be associated with a poorer overall survival. Noggin overexpression promoted the proliferation and colony formation of GC cells by promoting cell cycle progression. The knockdown of Noggin in HGC27 cells exerted an opposite effect on proliferation, colony formation and cell cycle progression. Noggin expression positively correlated with EGFR expression in both GC cell line models and The Cancer Genome Atlas human GC cohort. Targeting EGFR and its downstream pathways diminished cell proliferation which was promoted by Noggin. Furthermore, Noggin overexpression resulted in an enhanced nuclear translocation of ß­catenin, leading to an upregulation of EGFR. Thus, the findings of the present study demonstrate that Noggin promotes the proliferation of GC cells by upregulating EGFR and enhancing a vicious circle formed by ß­catenin, EGFR, ERK and Akt.

Efficacy of compatible acupoints and single acupoint versus sham acupuncture for functional dyspepsia: study protocol for a randomized controlled trial.

BACKGROUND: Acupoint selection is a key factor in the treatment of diseases and has not been well studied. The aim of this trial is to explore the differences in efficacy between compatible acupoints and a single acupoint for patients with functional dyspepsia (FD). METHODS: This randomized controlled trial will be conducted in the First Affiliated Hospital of Changchun University of Chinese Medicine in China. Two hundred and sixteen FD patients will be randomly assigned to the compatible acupoints group, single acupoint group, or sham acupuncture group. This trial will include a 1-week baseline period, a 4-week treatment period, and a 4-week follow-up period. During the 4-week treatment period, patients will receive 20 sessions of acupuncture (weekly cycles of one session per day for 5 consecutive days followed by a 2-day break). The primary outcome will be a change in the Nepean Dyspepsia Life Quality Index from baseline to after the 4-week treatment period. Secondary outcome measures will include the dyspeptic symptom sum score, Overall Treatment Effect questionnaire, and 36-item Short Form survey. Adverse events also will be recorded. Ultraweak photon emission and metabolomics tests will be performed at baseline and at the end of treatment to explore the mechanisms of the differences between compatible acupoints and a single acupoint. DISCUSSION: The results of this trial will allow us to compare the difference in efficacy between compatible acupoints and a single acupoint. The findings from this trial will be published in peer-reviewed journals. TRIAL REGISTRATION: Acupuncture-Moxibustion Clinical Trial Registry, AMCTR-IPC-18000176, registered on 4 March 2019; Chinese Clinical Trial Registry, ChiCTR1900023983, registered on 23 June 2019.

Application of three statistical models for predicting the risk of diabetes.

BACKGROUND: At present, the proportion of undiagnosed diabetes in Chinese adults is as high as 15.5%. People with diabetes who are not treated and controlled in time may have various complications, such as cardiovascular and cerebrovascular diseases and diabetic foot disorders, which not only seriously affect the quality of life of people with diabetes but also impose a heavy burden on families and society. Therefore, prevention and control of type 2 diabetes is of great significance. METHODS: We constructed a logistic regression model, a neural network model and a decision tree model to analyse the risk factors for type 2 diabetes and then compared the prediction accuracy of the different models by calculating the area under the relative operating characteristic (ROC) curve and back-inputting the data into the model. RESULTS: The prevalence of type 2 diabetes in 4177 subjects who were not diagnosed with type 2 diabetes was 9.31%. The most influential factors associated with type 2 diabetes were triglyceride (TG) ≥ 1.17 mmol/L (odds ratio (OR) =2.233), age ≥ 70 years (OR = 1.734), hypertension (OR = 1.703), alcohol consumption (OR = 1.674), and total cholesterol≥5.2 mmol/L (TC) (OR = 1.463). The prediction accuracies of the three prediction models were 90.8, 91.2, and 90.7%, respectively, and the areas under curve (AUCs) were 0.711, 0.780, and 0.698, respectively. The differences in the AUCs after back propagation (BP) of the neural network model, logistic regression model and decision tree model were statistically significant (P < 0.05). CONCLUSION: BP neural networks have a higher predictive power for identifying the associated risk factors of type 2 diabetes than the other two models, but it is necessary to select a suitable model for specific situations.

Analysis of influencing factor of coexisting prediabetes and prehypertension in adult residents of Jilin Province.

BACKGROUND: To explore the risk factors of coexisting prediabetes and prehypertension, to provide theoretical basis for early intervention. METHODS: A multi-stage stratified random cluster sampling method was used to randomly select adult residents from Jilin Province in 2013 for questionnaire surveys, physical examinations, and laboratory tests. RESULTS: The prevalence of coexisting prediabetes and prehypertension in Jilin Province was 11.3%. The binary Logistic regression results showed that age, sex, education, triglyceride (TG), BMI, waist circumference and alcohol consumption were the effects of factor coexisting prediabetes and prehypertension. CONCLUSION: It is important to pay attention to the early stage of hypertension and diabetes, control the transition from prehypertension and prediabetes to hypertension and diabetes, and improve the health of residents.

Reduced NOV expression correlates with disease progression in colorectal cancer and is associated with survival, invasion and chemoresistance of cancer cells.

Aberrant expression of nephroblastoma overexpressed (NOV) has been evident in certain malignancies. In the current study, we aim to investigate the role played by NOV in colorectal cancer (CRC). NOV expression was determined in a cohort of 359 CRC tissues and 174 normal colorectal tissues. Its impact on CRC cells was investigated using in vitro NOV knockdown and overexpression models. NOV transcripts were reduced in the CRC tumours compared with the paired adjacent normal colorectal tissues (p < 0.01) and was associated with distant metastases. NOV knockdown resulted in increased cell proliferation and invasion of RKO cells, whilst an opposite effect was seen in the HT115 NOV over expressing cells. A positive association between Caspase-3/-8 and NOV was seen in NOV knockdown and overexpression cell lines which contributed to the survival of serum deprived CRC cells. Further investigation showed that NOV regulated proliferation, survival and invasion through the JNK pathway. NOV knockdown in RKO cells reduced the responsiveness to 5-Fluorouracil treatment, whilst overexpression in HT115 cells exhibited a contrasting effect. Taken together, NOV is reduced in CRC tumours and this is associated with disease progression. NOV inhibits the proliferation and invasion of CRC cells in vitro. Inhibition of proliferation is mediated by a regulation of Caspase-3/-8, via the JNK pathway, which has potential for predicting and preventing chemoresistance.

Psoriasin promotes invasion, aggregation and survival of pancreatic cancer cells; association with disease progression.

Psoriasin (S100A7) is an 11-kDa small calcium binding protein initially isolated from psoriatic skin lesions. It belongs to the S100 family of proteins which play an important role in a range of cell functions including proliferation, differentiation, migration and apoptosis. Aberrant Psoriasin expression has been implicated in a range of cancers and is often associated with poor prognosis. This study examined the role of Psoriasin on pancreatic cancer cell functions and the implication in progression of the disease. Expression of Psoriasin was determined in a cohort of pancreatic tissues comprised of 126 pancreatic tumours and 114 adjacent non-tumour pancreatic tissues. Knockdown and overexpression of Psoriasin in pancreatic cancer cells was performed using specifically constructed plasmids, which either had anti-Psoriasin ribozyme transgene or the full length human Psoriasin coding sequence. Psoriasin knockdown and overexpression was verified using conventional RT-PCR and qPCR. The effect of manipulating Psoriasin expression on pancreatic cancer cell functions was assessed using several in vitro cell function assays. Local invasive pancreatic cancers extended beyond the pancreas expressed higher levels of Psoriasin transcripts compared with the cancers confined to the pancreas. Primary tumours with distant metastases exhibited a reduced expression of Psoriasin. Psoriasin overexpression cell lines exhibited significantly increased growth and migration compared to control cells. In addition, Psoriasin overexpression resulted in increased pancreatic cancer cell invasion which was associated with upregulation of matrix metalloproteinase-2 (MMP-2) and MMP-9. Overexpression of Psoriasin also promoted aggregation and survival of pancreatic cancer cells when they lost anchorage. Taken together, higher expression of Psoriasin was associated with local invasion in pancreatic cancers. Psoriasin expression is associated with pancreatic cancer cell growth, migration, cell-matrix adhesion, and invasion via regulation of MMPs. As such, the proposed implications of Psoriasin in invasion, disease progression and as a potential therapeutic target warrant further investigation.

Dual roles of protein tyrosine phosphatase kappa in coordinating angiogenesis induced by pro-angiogenic factors.

A potential role may be played by receptor-type protein tyrosine phosphatase kappa (PTPRK) in angiogenesis due to its critical function in coordinating intracellular signal transduction from various receptors reliant on tyrosine phosphorylation. In the present study, we investigated the involvement of PTPRK in the cellular functions of vascular endothelial cells (HECV) and its role in angiogenesis using in vitro assays and a PTPRK knockdown vascular endothelial cell model. PTPRK knockdown in HECV cells (HECVPTPRKkd) resulted in a decrease of cell proliferation and cell-matrix adhesion; however, increased cell spreading and motility were seen. Reduced focal adhesion kinase (FAK) and paxillin protein levels were seen in the PTPRK knockdown cells which may contribute to the inhibitory effect on adhesion. HECVPTPRKkd cells were more responsive to the treatment of fibroblast growth factor (FGF) in their migration compared with the untreated control and cells treated with VEGF. Moreover, elevated c-Src and Akt1 were seen in the PTPRK knockdown cells. The FGF-promoted cell migration was remarkably suppressed by an addition of PLCγ inhibitor compared with other small inhibitors. Knockdown of PTPRK suppressed the ability of HECV cells to form tubules and also impaired the tubule formation that was induced by FGF and conditioned medium of cancer cells. Taken together, it suggests that PTPRK plays dual roles in coordinating angiogenesis. It plays a positive role in cell proliferation, adhesion and tubule formation, but suppresses cell migration, in particular, the FGF-promoted migration. PTPRK bears potential to be targeted for the prevention of tumour associated angiogenesis.

Expression of phospholipase C isozymes in human breast cancer and their clinical significance.

Phospholipase C (PLC) regulates a number of cellular behaviours including cell motility, cell transformation, differentiation and cell growth. PLC plays a regulatory role in cancer cells partly by acting as signalling intermediates for cytokines such as EGF and interleukins. The current study examined the expression of the PLC isozymes in human breast cancer and corresponding clinical relevance. Transcript levels of human PLC-α, -ß1, -δ, -ε, and -γ1 in human breast cancer tissues were quantitatively determined by real-time PCR. Immunochemical staining was performed for PLC-δ. The clinical relevance was analysed with clinic pathological information. Mammary tissues widely expressed PLC-α, -ß1, -δ, -ε, and -γ1. Significantly high levels of PLC -ß1 and -ε were seen in breast cancer tissues in comparison with normal mammary gland tissues. PLC-γ1 however, showed marginally low levels in tumour tissues. No significant difference was seen in the expression of the PLC isozymes in tumours with lymph node metastases. Moderately and poorly differentiated breast tumours (grade 2 and grade 3) had significantly higher levels of PLC-γ1, compared with well differentiated tumours. High levels of PLC-δ were significantly correlated with a shorter disease-free survival. The altered expression of other isozymes had no correlation with the survival. It is concluded that mammary tissues differentially expressed PLC isozymes. These isozymes have certain implications in the disease development and progression, with PLC-δ showing a significant correlation with shorter disease-free survival.

Prostate Apoptosis Response-4 (PAR4) Suppresses Growth and Invasion of Breast Cancer Cells and Is Positively Associated with Patient Survival.

BACKGROUND: Prostate apoptosis response-4 (PAR4) plays an important role in apoptosis and survival of cancer cells. The current study aimed to further elucidate its role in breast cancer. MATERIALS AND METHODS: PAR4 expression in human breast cancer tissue was examined using quantitative polymerase chain reaction (qPCR) and immunohistochemical staining (IHC). Plasmids containing full-length human PAR4 coding sequence were used to overexpress PAR4 in breast cancer cells and the effect on cellular functions was examined using both in vitro functional assays and an in vivo murine model. RESULTS: Patients with low PAR4 transcript levels had poorer overall survival. PAR4 expression may be associated with differential expression of oestrogen receptors α and ß in the tumours. Overexpression of PAR4 in MDA-MB-231 cells resulted in reduced cell growth and invasion, and also reduced in vivo tumour growth. CONCLUSION: Decreased PAR4 expression in breast cancer is associated with shorter survival. PAR4 suppresses growth and invasiveness of breast cancer cells.

Reduced RanBPM Expression Is Associated with Distant Metastasis in Gastric Cancer and Chemoresistance.

AIM: Ran binding protein M (RanBPM) is a ubiquitous, nucleocytoplasmic protein that serves as a scaffolding molecule. This study aimed to investigate the role of RanBPM in gastric cancer. MATERIALS AND METHODS: RanBPM expression in human gastric cancer tissue samples was analyzed using real-time polymerase chain reaction. The effect of RanBPM on cellular functions was examined in RanBPM-knockdown gastric cells and with in vitro cell functional assays. RESULTS: Gastric tumors with distant metastases expressed lower levels of RanBPM transcripts compared to tumours without detectable metastases (p=0.036). RanBPM knockdown in gastric cancer cells reduced adhesion and promoted survival of gastric cancer cells after exposure to methotrexate and fluorouracil. CONCLUSION: RanBPM levels were reduced in gastric tumors with distant metastases. This suggests that loss of RanBPM expression may play an important role in gastric cancer tumor development and metastasis. Reduced RanBPM expression is also associated with chemoresistance of gastric cancer cells.

MTA1 Is Up-regulated in Colorectal Cancer and Is Inversely Correlated with Lymphatic Metastasis.

BACKGROUND: Metastasis-associated protein 1 (MTA1) plays an important role in tumourigenesis and progression of certain cancer types. In the current study, we analyzed the relationship between MTA1 expression and disease progression of colorectal cancer (CRC). MATERIALS AND METHODS: CRC tissues (n=93) and adjacent normal colorectal tissues (n=70) were analyzed by quantitative real-time polymerase chain reaction. MTA1 knockdown was established in RKO and HT115 cells using MTA1 siRNA. RESULTS: The expression of MTA1 was significantly increased in CRC tissues compared to paired normal colorectal tissues, but decreased expression of MTA1 was correlated with poor prognosis (higher lymph node involvement stage, TNM stage, local invasion and recurrence) that was associated with increased expression of VEGFC and -D and the receptor VEGFR3. CONCLUSION: MTA1 is up-regulated in CRC. MTA1 expression is inversely associated with lymphatic metastases and the expression of VEGFC, VEGFD and VEGFR3.

YangZheng XiaoJi exerts anti-tumour growth effects by antagonising the effects of HGF and its receptor, cMET, in human lung cancer cells.

BACKGROUND: Hepatocyte growth factor (HGF) is a cytokine that has a profound effect on cancer cells by stimulating migration and invasion and acting as an angiogenic factor. In lung cancer, the factor also plays a pivotal role and is linked to a poor outcome in patients. In particular, HGF is known to work in combination with EGF on lung cancer cells. In the present study, we investigated the effect of a traditional Chinese medicine reported in cancer therapies, namely YangZheng XiaoJi (YZXJ) on lung cancer and on HGF mediated migration and invasion of lung cancer cells. METHODS: Human lung cancer cells, SKMES1 and A549 were used in the study. An extract from the medicine was used. Cell migration was investigated using the EVOS and by ECIS. Cell-matrix adhesion and in vitro invasion were assessed. In vivo growth of lung cancer was tested using an in vivo xenograft tumour model and activation of the HGF receptor in lung tumours by an immunofluorescence method. RESULTS: Both lung cancer cells increased their migration in response to HGF and responded to YZXJ by reducing their speed of migration. YZXJ markedly reduced the migration and in vitro invasiveness induced by HGF. It worked synergistically with PHA665752 and SU11274, HGF receptor inhibitors on the lung cancer cells both on HGF receptor activation and on cell functions. A combination of HGF and EGF resulted in a greater increase in cell migration, which was similarly inhibited by YZXJ, and in combination with the HGF receptor and EGF receptor inhibitors. In vivo, YZXJ reduced the rate of tumour growth and potentiated the effects of PHA665752 on tumour growth. It was further revealed that YZXJ significantly reduced the degree of phosphorylation of the HGF receptor in lung tumours. CONCLUSION: YZXJ has a significant role in reducing the migration, invasion and in vivo tumour growth of lung cancer and acts to inhibit the migratory and invasive effects induced by HGF and indeed by HGF/EGF. This effect is likely attributed to the inhibition of the HGF receptor activation. These results indicate that YZXJ has a therapeutic role in lung cancer and that combined strategy with methods to block HGF and EGF should be considered.

Knockdown of WAVE3 impairs HGF induced migration and invasion of prostate cancer cells.

BACKGROUND: The WASP (Wiskott-Aldrich syndrome protein) and WAVE (WASP Verpolin homologous) family of proteins are structurally related and responsible for regulation of actin polymerization through their interaction with actin related proteins 2&3 (ARP 2/3). WAVE-3 has exhibited an association with disease progression and poorer prognosis of certain malignancies. In the current study, we determined the role of WAVE-3 in hepatocyte growth factor induced cellular changes including cell matrix interaction, invasion and cellular motility, and pathways that may be responsible for the changes in prostate cancer cells. METHODS: We used hammer head ribozymes to knock down the expression of WAVE-3 in PC-3 prostate cancer cell line. In vitro cellular functional assays including growth, invasion, adhesion, motility and invasion, were performed to assess the effects of WAVE-3 knock down. Further experimentation was performed to investigate the role of different pathway through expression and phosphorylation status of various intermediate proteins. RESULTS: WAVE-3 knockdown reduced invasive potential and motility of prostate cancer cells. Following addition of HGF, control cells showed significantly increased invasion and motility (p value <0.5) and marked increase in cellular growth. However, WAVE-3 knockdown cell line failed to show any increase in these trends (p value <0.5) except increased growth compared with control cells. Further experiments revealed that HGF-induced activation of Paxillin was weakened by the knockdown of WAVE-3. Our study also indicated that reduced invasiveness following WAVE-3 knockdown, may be related to reduce activity of MMP-2. CONCLUSIONS: Our studies suggest a vital role of WAVE-3 in HGF induced invasion and migration in which Paxillin and MMP-2 are involved. Further study will shed light on its potential as therapeutic target to suppress local invasion and metastasis of prostate cancer cells.

Expression of Sonic Hedgehog (SHH) in human lung cancer and the impact of YangZheng XiaoJi on SHH-mediated biological function of lung cancer cells and tumor growth.

Sonic Hedgehog (SHH) is a protein that is aberrantly expressed in various human tumors. SHH and its signaling molecules have been indicated as potential therapeutic targets. In the present study, we evaluated the expression of SHH transcript in human non-small cell lung cancer (NSCLC) tissues and investigated the impact of inhibiting SHH together with a traditional Chinese medicine formula, YangZheng XiaoJi (YZXJ), on the function and growth of lung cancer cells. Human NSCLC tissues had significantly higher levels of the SHH transcript compared matched normal lung tissues (n=83). TNM2 tumors and tumors with pleural invasion had higher levels than TNM1 and non-invasive tumors. High SHH levels were associated with a shorter overall survival (OS) of the patients. A SHH inhibitor, cyclopamine, and YZXJ alone or in combination had a marked inhibitory effect on cellular invasion and cellular migration of human lung cancer cells, A549 and SKMES1. YangZheng XiaoJi and its combination with cyclopamine also significantly reduced the growth of lung tumors in vivo together with a reduction of SHH and smoothened (Smo) proteins in the lung tumors. The present study provides evidence that blocking SHH by way of small inhibitor and by YangZheng XiaoJi has a profound influence on lung cancer cells as seen by in vitro invasion and cell migration and in vivo tumor growth. Together with the aberrant expression of SHH in NSCLC tumors in the patients, it is suggested that SHH is a potential target for therapies for NSCLC.