Comparison of Inflammation-Based Prognostic Scores Associated with the Prognostic Impact of Adenocarcinoma of Esophagogastric Junction and Upper Gastric Cancer.

BACKGROUND: Several inflammation-based prognostic scores have a prognostic value in patients with various cancers. This study investigated the prognostic value of various inflammation-based prognostic scores in patients who underwent a surgery for adenocarcinoma of the esophagogastric junction (AEG) and upper gastric cancer (UGC). METHODS: We reviewed data of 206 patients who underwent surgery for AEG and UGC. We calculated neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), Glasgow Prognostic Score (GPS), modified GPS (mGPS), C-reactive protein (CRP)/albumin (Alb) ratio, prognostic index (PI), and prognostic nutritional index (PNI) and analyzed the relationship between these biomarkers and postoperative prognosis. RESULTS: In multivariate analyses for overall survival, mGPS (P = 0.0337, hazard ratio [HR] = 5.211), PI (P = 0.0002, HR = 21.20), and PNI (P < 0.0001, HR = 6.907) were identified as independent predictive factors. A multivariate analysis for recurrence-free survival showed that only PI (P = 0.0006, HR = 11.89) and PNI (P = 0.0002, HR = 4.972) were independent predictive factors among the above-mentioned inflammation-based prognostic scores. CONCLUSIONS: In various inflammation-based prognostic scores, PI and PNI were more strongly associated with poor prognosis in patients who underwent surgery for AEG and UGC.

Clinical Significance of SIP1 and E-cadherin in Patients with Esophageal Squamous Cell Carcinoma.

BACKGROUND: Epithelial-mesenchymal transition (EMT), when epithelial cells convert to mesenchymal cells, influences cancer invasion and metastasis. Smad interacting protein 1 (SIP1) is an EMT trigger, which is inversely correlated with E-cadherin in some carcinomas. To elucidate the role of SIP1 in esophageal squamous cell carcinoma (ESCC), the status of EMT and the clinicopathological features were evaluated. METHODS: Immunohistochemical (IHC) analyses of 111 human ESCC tissue specimens for SIP1 and E-cadherin were performed, and the relationships between the expression and clinicopathological features were evaluated. RESULTS: IHC analyses of esophageal tumors showed the expression of SIP1 and E-cadherin to be significantly inversely correlated. Significant correlations between the SIP1 expression and clinicopathological variables such as differentiation, depth of invasion, vascular invasion, and pathological stage were also seen. Conversely, tumors with a weak expression of E-cadherin tended to exhibit greater histological differentiation. Logistic regression analyses revealed a positive SIP1 expression, lymphatic invasion, and vascular invasion to be factors predicting lymph node (LN) metastasis. Univariate survival analyses revealed a positive SIP1 expression predicted a poorer overall survival than a negative expression. CONCLUSION: These results suggest that SIP1 is correlated with LN metastasis and may therefore be an independent marker for metastasis in patients with ESCC.

Podoplanin is expressed at the invasive front of esophageal squamous cell carcinomas and is involved in collective cell invasion.

The expression of podoplanin is reportedly involved in collective cell invasion, which is independent from the epithelial-mesenchymal transition (EMT). We focused on the expression of podoplanin in esophageal squamous cell carcinomas (ESCC) and investigated the correlation of podoplanin and EMT-related markers, and evaluated its prognostic significance. Five ESCC cell lines were subjected to western blot analysis for podoplanin and EMT markers. The effects of podoplanin on EMT and carcinoma invasion were evaluated with wound healing assays, invasion assays and 3-D culture. Transfection of ectopic podoplanin into a podoplanin-negative ESCC cell line (TE-15) induced cell migration and invasive activity (P < 0.001 and P < 0.05, respectively) without downregulation of E-cadherin. In contrast, transfection of si-podoplanin RNA into a podoplanin-positive ESCC cell line (TE-13) reduced cell migration and invasive activity (P < 0.05). We reviewed 101 patients who had undergone esophagectomy for ESCC. Podoplanin expression was observed in 58 patients (57.4%), and positive expression was positively correlated with expression of E-cadherin (P < 0.01), deeper wall invasion (P < 0.01), venous invasion (P < 0.05) and poorer prognosis (P < 0.01). Multivariate Cox analysis revealed that expression of podoplanin was a significant and independent unfavorable predictor of survival (P < 0.05). These data suggest that podoplanin is significantly associated with and likely contributes to ESCC invasion in the absence of EMT.

Outcome and status of microsatellite stability in Japanese atomic bomb survivors with early gastric carcinoma.

BACKGROUND: In the decade after the 1945 atomic bombing of Hiroshima, a high incidence of leukemia was observed among atomic bomb survivors. However, the incidence of other cancers gradually increased, while that of leukemia decreased after this period. We evaluated the clinical outcome of early gastric cancer and microsatellite stability over a long-term period in atomic bomb survivors. METHODS: The results of surgical treatment for early gastric cancer were reviewed for 117 atomic bomb survivors and 394 control patients between 1995 and 2006. In addition, immunohistochemical staining for hMSH2 and hMLH1 expression was performed to evaluate the status of microsatellite stability in 57 atomic bomb survivors and 82 control patients. RESULTS: The long-term survival rate for early gastric cancer in atomic bomb survivors was significantly lower than that in control patients (p < 0.01). Multivariable analysis revealed that age and sex were significant and independent prognostic factors for early gastric cancer. Defective hMSH2 and/or hMLH1 expression was also significantly higher in survivors than in control patients (p < 0.001). Logistic regression analysis revealed that atomic bomb survivorship was related to defective hMSH2 and/or hMLH1 expression. CONCLUSIONS: The prognosis of early gastric cancer in atomic bomb survivors was poor and was related to age and sex, rather than to being an atomic bomb survivor. Furthermore, a higher rate of defective hMSH2 and/or hMLH1 expression was observed in the survivors.

Surgery after preoperative chemotherapy for patients with unresectable advanced gastric cancer.

OBJECTIVE: The study aimed to evaluate the efficacy of surgery after preoperative chemotherapy for unresectable advanced gastric cancer. METHOD: Twenty patients with disappeared peritoneal dissemination or decreased lymph node metastasis by systemic chemotherapy underwent surgery (group S), while 14 with peritoneal dissemination or lymph nodes >N2 (group C) received continuous systemic chemotherapy. Among group S patients, 15 underwent a curative resection (group R0), while the other 5 did not microscopically undergo a curative resection (group R1). RESULTS: The median survival time for all patients was 535 days. Survival time was significantly dependent on the chemotherapy response (p < 0.002). The survival period in group S was significantly longer than that in group C (median survival time 747 vs. 476 days; p < 0.02). The relapse-free survival was 299 days in group S. In particular, the survival period of patients who underwent R0 surgery by preoperative chemotherapy was significantly longer than that of group R1 patients (median survival time 794 vs. 485 days; p < 0.02). Multivariate analysis revealed that R0 surgery was a significant and independent prognostic factor. CONCLUSION: Surgery was effective for advanced gastric cancer patients when performed as R0 resection following the disappearance of non-curative factors by preoperative chemotherapy.

Prognostic markers for immunochemotherapy using tegafur -uracil (UFT) and protein-bound polysaccharide K (PSK).

AIM/BACKGROUND: We previously reported that PSK-induced lymphocyte blastogenesis reaction (PSK-stimulation index; PSK-SI) may be a prognostic marker for immunochemotherapy using PSK in gastrointestinal cancer patients. In this study we evaluated the usefulness of PSK-SI as a prognostic marker for PSK therapy at higher and lower serum immunosuppressive acidic protein (IAP) levels. PATIENTS AND METHODS: 98 gastric and 135 colorectal cancer patients were analyzed. PSK-SI and serum IAP levels were measured preoperatively. After operation, patients received UFT and PSK for two years. RESULTS: There were no differences between patients with higher and those with lower PSK-SI with respect to the clinicopathological factors. In patients with higher serum IAP levels (> or = 500 microg/ml), recurrence-free survival (RFS) and overall survival (OS) were apparently more favorable in the higher PSK-SI group (gastric cancer; > or = 1.75, colorectal cancer; > or = 2.1) than in lower PSK-SI group, although the differences were not significant. CONCLUSION: Serum IAP levels and PSK-SI may be useful markers for prediction of response to immunochemotherapy using PSK, although further studies are necessary.

Plasma D-dimer level as a mortality predictor in patients with advanced or recurrent colorectal cancer.

OBJECTIVE: Plasma D-dimer levels are elevated in patients with a variety of solid tumors. Recently, it has been reported that the level before curative surgery is a prognostic factor for colorectal cancer (CRC). We investigated whether the plasma D-dimer level before systemic chemotherapies is a predictor for advanced or recurrent unresectable CRC. METHODS: This study included 42 patients treated with systemic chemotherapies for advanced or recurrent unresectable CRC. Variables including clinicopathological factors, plasma D-dimer levels and the modified Glasgow Prognostic Factor Score (mGPS) were evaluated. RESULTS: The plasma D-dimer level was closely related to the mGPS. Survival was shorter for patients with plasma D-dimer levels >5 µg/ml than for those with lower levels. Compared with an mGPS of 0 or 1, an mGPS of 2 was predictive of poor prognosis (p < 0.0001). Old age, advanced stage, plasma D-dimer level and mGPS were significantly associated with mortality, but plasma D-dimer level was the only independent risk factor in multivariate analysis, and was significant related to the clinical response to chemotherapy (p < 0.05). CONCLUSIONS: Survival was significantly shorter in patients with elevated plasma D-dimer levels having advanced or recurrent CRC. The plasma D-dimer level before systemic chemotherapies was an independent mortality predictor.

Biological mechanism and clinical effect of protein-bound polysaccharide K (KRESTIN(®)): review of development and future perspectives.

The mechanism of action of protein-bound polysaccharide K (PSK; KRESTIN(®)) involves the following actions: (1) recovery from immunosuppression induced by humoral factors such as transforming growth factor (TGF)-ß or as a result of surgery and chemotherapy; (2) activation of antitumor immune responses including maturation of dendritic cells, correction of Th1/Th2 imbalance, and promotion of interleukin-15 production by monocytes; and (3) enhancement of the antitumor effect of chemotherapy by induction of apoptosis and inhibition of metastasis through direct actions on tumor cells. The clinical effectiveness of PSK has been demonstrated for various cancers. In patients with gastric or colorectal cancer, combined use of PSK with postoperative adjuvant chemotherapy prolongs survival, and this effect has been confirmed in multiple meta-analyses. For small-cell lung carcinoma, PSK in conjunction with chemotherapy prolongs the remission period. In addition, PSK has been shown to be effective against various other cancers, reduce the adverse effects of chemotherapy, and improve quality of life. Future studies should examine the effects of PSK under different host immune conditions and tumor properties, elucidate the mechanism of action exhibited in each situation, and identify biomarkers.

In-hospital mortality after a surgical resection for esophageal cancer: analyses of the associated factors and historical changes.

BACKGROUND: Resections for esophageal cancer are invasive, with high mortality and morbidity rates. The object of this study was to clarify the factors associated with in-hospital death while also evaluating any associated historical changes in the characteristics of such deaths. METHODS: The factors associated with mortality were examined by logistic regression analysis in 1106 patients who underwent an esophagectomy for esophageal cancer. The historical changes in the characteristics of in-hospital deaths were also evaluated. RESULTS: A multivariate analysis revealed that not only undergoing an esophagectomy before 1979, but also a patient's age (odds ratio 1.070 for every increase in age by year) and an incomplete resection (odds ratio 2.265) were independent factors associated with in-hospital death. The in-hospital mortality rates were 16.1%, 5.8%, 2.5%, and 3.1%, while the 30-day mortality rates were 9.2%, 2.2%, 0.8%, and 0.3% during 1964-1979, the 1980s, the 1990s, and the 2000s, respectively. Eight patients had preoperative comorbidities among 11 patients who died in the hospital after 1997. The mortality rate was 5.5% in patients with any comorbidities, while it was 1.3% in patients without any comorbidities (P = 0.026). The most common direct cause of in-hospital death was previous pulmonary complications; however, cancer progression has recently become the most common cause. CONCLUSIONS: To prevent in-hospital mortality after an esophagectomy, strict indications for surgery and careful perioperative management are important, especially in high-risk patients with advanced esophageal cancer.

Perturbation of transforming growth factor (TGF)-beta1 association with latent TGF-beta binding protein yields inflammation and tumors.

Transforming growth factor-beta (TGF-beta) activity is controlled at many levels including the conversion of the latent secreted form to its active state. TGF-beta is often released as part of an inactive tripartite complex consisting of TGF-beta, the TGF-beta propeptide, and a molecule of latent TGF-beta binding protein (LTBP). The interaction of TGF-beta and its cleaved propeptide renders the growth factor latent, and the liberation of TGF-beta from this state is crucial for signaling. To examine the contribution of LTBP to TGF-beta function, we generated mice in which the cysteines that link the propeptide to LTBP were mutated to serines, thereby blocking covalent association. Tgfb1(C33S/C33S) mice had multiorgan inflammation, lack of skin Langerhans cells (LC), and a shortened lifespan, consistent with decreased TGF-beta1 levels. However, the inflammatory response and decreased lifespan were not as severe as observed with Tgfb1(-/-) animals. Tgfb1(C33S/C33S) mice exhibited decreased levels of active TGF-beta1, decreased TGF-beta signaling, and tumors of the stomach, rectum, and anus. These data suggest that the association of LTBP with the latent TGF-beta complex is important for proper TGF-beta1 function and that Tgfb1(C33S/C33S) mice are hypomorphs for active TGF-beta1. Moreover, although mechanisms exist to activate latent TGF-beta1 in the absence of LTBP, these mechanisms are not as efficient as those that use the latent complex containing LTBP.

Surgical removal of a denture with sharp clasps impacted in the cervicothoracic esophagus: report of three cases.

We report three cases of successful surgical removal of a denture with sharp clasps impacted in the cervical esophagus. Patient 1 was a 57-year-old woman institutionalized for over 30 years for schizophrenia, patient 2 was a 62-year-old man hospitalized for brain paralysis, and patient 3 was a 64-year-old man suffering cerebral hemorrhage sequelae. All three patients swallowed a denture accidentally. Chest X-rays showed the denture with sharp clasps in the cervicothoracic region of the esophagus, and endoscopy revealed that it was lodged in the esophageal mucosa. The denture was subsequently removed by cervical esophagotomy. All three patients had a good clinical postoperative course without any complications. Thus, we recommend surgery via a cervical approach to remove a denture with sharp clasps impacted in the cervicothoracic esophagus, with intraoperative endoscopic examination for esophageal injury.

Simultaneous total gastrectomy and endovascular repair of an abdominal aortic aneurysm: report of a case.

We herein present the case of a 66-year-old man with both gastric cancer and an infrarenal abdominal aneurysm. The patient's medical history included bladder cancer, chronic renal failure, and ischemic heart disease. We performed a simultaneous endovascular aneurysm repair (EVAR) and total gastrectomy. Following the procedure, the patient remained in the intensive care unit for 3 days. Oral feeding was resumed on postoperative day 7, and the patient was discharged from the hospital on postoperative day 13 with no complications. Despite the patient's medical problems and higher operative risk, he tolerated simultaneous EVAR and total gastrectomy, and had a good outcome after undergoing these simultaneous procedures.

High expression of BUBR1 is one of the factors for inducing DNA aneuploidy and progression in gastric cancer.

Gastric cancers show high frequency of DNA aneuploidy, a phenotype of chromosomal instability. It is suggested that the abnormal spindle assembly checkpoint is involved in DNA aneuploidy, but the underlying mechanism is still unclear. We studied the mechanism by assessing the expression of BUBR1 in gastric cancer. The DNA ploidy patterns of 116 gastric cancer samples obtained from the Department of Surgery and Science at Kyushu University Hospital were analyzed. Of those, DNA aneuploidy was seen in 70 (60.3%) cases of gastric cancer. The expression of BUBR1 was studied by immunohistochemistry in 181 gastric cancer samples and by real-time RT-PCR in several gastric cancer cell lines. Ninety-one (50.3%) cases had high expression of BUBR1 and those cases correlated significantly with DNA aneuploidy (P < 0.05). Also high expression of BUBR1 cases had significant correlation with deep invasion, lymph node metastasis, liver metastasis, and poor prognosis. In gastric cancer cell lines, high expression of BUBR1 had a significant relationship with DNA aneuploidy (P < 0.05). Then, gastric cancer cell lines MKN-28 and SNU-1 were transfected with full-length BUBR1 to observe the significance of the change in BUBR1 expression. Enforced expression of BUBR1 resulted in changes to the ploidy pattern and high Ki-67 expression. Collectively, our clinical and in vitro data indicate that high expression of BUBR1 may be one of causative factors for the induction of DNA aneuploidy and progression of gastric cancer.

In vitro and in vivo evidence for shear-induced activation of latent transforming growth factor-beta1.

Transforming growth factor-beta1 (TGF-beta1) has potent physiologic and pathologic effects on a variety of cell types at subnanomolar concentrations. Platelets contain 40 times as much TGF-beta1 as other cells and secrete it as an inactive (latent) form in complex with latency-associated peptide (LAP), which is disulfide bonded via Cys33 to latent TGF-beta binding protein 1 (LTBP-1). Little is known about how latent TGF-beta1 becomes activated in vivo. Here we show that TGF-beta1 released from platelets or fibroblasts undergoes dramatic activation when subjected to stirring or shear forces, providing a potential mechanism for physiologic control. Thiol-disulfide exchange appears to contribute to the process based on the effects of thiol-reactive reagents and differences in thiol labeling of TGF-beta1 before and after stirring or shear. Activation required the presence of LTBP, as TGF-beta1 contained in complex with only LAP could not be activated by stirring when studied as either a recombinant purified protein complex or in the platelet releasates or sera of mice engineered to contain an LAP C33S mutation. Release and activation of latent TGF-beta1 in vivo was demonstrated in a mouse model 5 minutes after thrombus formation. These data potentially provide a novel mechanism for in vivo activation of TGF-beta1.

Alcohol drinking, cigarette smoking, and the development of squamous cell carcinoma of the esophagus: epidemiology, clinical findings, and prevention.

Both cigarette smoking and alcohol drinking are well-established risk factors for esophageal squamous cell carcinoma (ESCC), and the relationship of dose to cancer risk has already been described. Furthermore, the synergistic effect of these two factors has been reported. Our case-control study revealed the odds ratio of ESCC to be 50.1 for those who were both heavy smokers and heavy drinkers in comparison to people who neither drank nor smoked. In patients with ESCC, head and neck cancers as well as dysplastic lesions are frequently observed. Heavy smoking and heavy drinking are closely related to such multicentric carcinogenesis events in the upper aerodigestive tract (UADT), including the esophagus and head andneck region. Polymorphisms in acetaldehyde dehydrogenase 2 (ALDH2) are reported to be a key event in deciding individual susceptibility to UADT cancer. Patients with inactive ALDH2, in whom facial flushing is usually observed after the drinking of alcohol, are at high risk for ESCC as well as multiple UADT cancers. For the early detection of the disease, effective follow up using endoscopy with Lugol staining or narrow band imaging endoscopy is strongly recommended for high-risk populations, such as smokers, heavy drinkers, people with experience of flushing after the drinking of alcohol, and patients with UADT cancer.

Unique variation of the hepatic artery identified on preoperative three-dimensional computed tomography angiography in surgery for gastric cancer: report of a case.

Hepatic artery injury is one complication associated with surgery for gastric cancer. This complication does not occur frequently, but it can cause serious problems. Anatomical variations of the hepatic arteries are thought to be a factor in such injuries. Recognizing vascular variations before the operation is thus very important. This report presents a case with a rare variation of the hepatic arteries identified on three-dimensional computed tomography (3D-CT) angiography before gastric cancer surgery. Hepatic artery injury was avoided as a result of the recognition of this extremely rare variation. Preoperative 3D-CT angiography is useful for preventing the complications associated with hepatic artery injury during surgery for gastric cancer.

Impact of perioperative peripheral blood values on postoperative complications after esophageal surgery.

PURPOSE: Prediction of the postoperative course of esophagectomy is an important part of the strict perioperative management of patients undergoing surgery for esophageal cancer. METHODS: To evaluate their clinical importance, peripheral blood values, including white blood cell count (WBC), lymphocyte count, and the levels of total protein, transferrin, factor XIII, D-dimer, fibrin, and fibrinogen degradation products (FDP) were measured before and after esophagectomy for esophageal cancer in 24 patients. RESULTS: The preoperative WBC and the pre- and postoperative lymphocyte count were decreased remarkably in patients who received preoperative chemoradiotherapy. The values of perioperative serum transferrin were significantly lower in patients with postoperative pneumonia than in those without. The activity of plasma factor XIII was suppressed on postoperative day (POD) 7 in patients with pneumonia and on POD 14 in patients with leakage. CONCLUSIONS: These results suggest that patients who receive preoperative chemoradiotherapy are potentially immunosuppressed, the preoperative serum transferrin level is a possible predictive marker of postoperative pneumonia, and suppression of factor XIII activity is related to anastomotic insufficiency.

Laparoscopic sleeve gastrectomy performed in a morbidly obese patient with gastrointestinal stromal tumor: a case report and literature review.

BACKGROUND: Gastrointestinal stromal tumor (GIST) is the most frequent submucosal tumor, and with advancements of diagnostic modalities, the incidence of GIST cases diagnosed have increased. Similarly, prevalence of morbid obesity has also rapidly increased over the past decade. Notably, the incidence of GIST in obese patients was reported to be more frequent as compared to the general population. Despite local resection being the first choice for GIST treatment, extensive surgery should also be considered depending on the tumor size and location. Laparoscopic sleeve gastrectomy (LSG), the most popular bariatric procedure, could also be a concomitant treatment option for both morbid obesity and GIST when the tumor is contained within LSG the excision range. There are, however, few reports about LSG planned for GIST preoperatively. CASE PRESENTATION: A morbidly obese 46-year-old Japanese male (body weight of 105.4 kg, body mass index (BMI) of 36.6 kg/m2) was diagnosed with an intramural GIST in the gastric fundus. Because of his extreme visceral fat dominated obesity (visceral fat area of 386 cm2), in addition to the size and location of the tumor, we determined that it would be difficult to perform local resection. We planned LSG as a concomitant treatment for both GIST and morbid obesity. After the preoperative examination and 6 months of weight control, the patient lost enough weight to undergo LSG safely. Keeping enough distance away from the tumor, which we observed with an endoscope, we performed LSG to successfully resect the tumor. The patient was discharged uneventfully. Weight loss was successful as his BMI was 21.0 kg/m2 at 3 months post-surgery. CONCLUSION: We successfully performed LSG in a morbidly obese patient with a large GIST. This is the largest GIST concomitantly resected with LSG reported within current literature.

Activin a causes cancer cell aggressiveness in esophageal squamous cell carcinoma cells.

BACKGROUND: Expression of activin A is associated with lymph node metastasis and clinical stage in esophageal cancer. METHODS: To clarify the aggressive behavior of tumors with high activin A expression, we used the beta subunit of activin A to establish stable activin betaA (Act-betaA)-transfected carcinoma cells in two human esophageal carcinoma cell lines, KYSE110 and KYSE140. The biological behavior of these cells was compared with that in mock-transfected cells from the same cell lines. We focused our attention on cell growth and tumorigenesis, and proliferation and apoptosis. RESULTS: Both Act-betaA-transfected carcinoma cell lines showed a higher growth rate than the mock-transfected carcinoma cells. In an in vitro invasion assay and a xenograft analysis, the Act-betaA-transfected carcinoma cells showed far higher proliferation in vitro and a higher potency for tumorigenesis in vivo, respectively. Moreover, in an analysis of apoptosis via Fas stimulation, the Act-betaA-transfected carcinoma cells showed a higher tolerance to apoptosis compared with the mock-transfected carcinoma cells. Moreover, anti-activin-neutralizing antibody-treated squamous cell cancer cell lines inhibited their migration. CONCLUSIONS: Collectively, these data indicate that continuous high expression of activin A in esophageal carcinoma cells is not related to tumor suppression, but rather to tumor progression in vitro and in vivo. The inhibition of activin might be one of the methods to attenuate tumor aggressiveness.

Activin A enhances MMP-7 activity via the transcription factor AP-1 in an esophageal squamous cell carcinoma cell line.

Activin A, a member of the transforming growth factor beta (TGF-beta) superfamily, is often overexpressed in solid carcinomas. We have previously reported that the expression of activin A is associated with lymph node metastasis in esophageal cancer. In the current study, our goal was to clarify the molecular mechanisms underlying the aggressive behavior of tumors expressing high levels of activin A. Using cDNA microarrays, the gene expression profile of a human esophageal carcinoma cell line (KYSE170) stably transfected with activin betaA (Act-betaA, a subunit of activin A) was compared with those of control human esophageal carcinoma cell lines. We found that expression of MMP-7 was higher in the Act-betaA transfectants than in the control cells. To reveal the mechanism of expression of MMP-7 mediated by activin A, we evaluated mRNA expression of MMP-7 and Act-betaA with or without activin A neutralizing antibody, using real-time PCR and Northern blot analysis. We also performed promoter analysis of the MMP-7 promoter and assessed c-Jun and Smad2/3 expression. MMP-7 expression in the transfectants was correlated with the level of Act-betaA expression and was reduced by activin A neutralizing antibody. The Act-betaA transfectants had higher MMP-7 promoter activity than control cells. MMP-7 promoter activity was not affected by mutation in the Smad binding site, while mutation of the AP-1 binding site did reduce activity. Moreover, the expression of c-Jun was increased in Act-betaA transfectants. These results indicate that activin A may modulate the expression of MMP-7 via AP-1 and not through Smad2/3.