Chunguang Li

OCT4 Positively Regulates Survivin Expression to Promote Cancer Cell Proliferation and Leads to Poor Prognosis in Esophageal Squamous Cell Carcinoma

Background OCT4 and Survivin are important factors for cancer cell proliferation, renewal and dedifferentiation, and correlate with resistance to radiotherapy and chemotherapy in most human cancers, but their regulatory mechanisms are not well known. Methodology/Principal Findings In this study, 50 patients with esophageal squamous cell carcinoma (ESCC) were retrospectively analyzed. OCT4 was expressed in 13 cases (26%), and survivin was positively expressed in 31 cases (62%), examined by immunochemistry. OCT4 was found to be an independent predictive factor for median survival time, and the patients from the subgroup with both high expression of OCT4 and Survivin had the worst prognosis investigated by log-rank test. To further explore the molecular regulatory mechanism between OCT4 and Survivin, we constructed the specific small hairpin RNA (shRNA)-expressing vectors targeting OCT4 or/and Survivin and manipulated the expression of OCT4 and Survivin. By Western blotting and RT-PCR, we found that OCT4 could up-regulate Survivin expression in the esophageal cancer cell lines Eca109 and TE1. Simultaneously knockdown of OCT4 and Survivin expression induced cell apoptosis and G2-phase decrease of cell cycle by flow cytometry, and finally exerted an enhanced anti-proliferation potency in Eca109 and TE1 cell lines by MTT assay. Conclusions This study shows that OCT4 and Survivin expression were correlated with poor survival in patients with ESCC. OCT4 and Survivin may be regarded as targets in ESCC biotherapy.

OCT4 increases BIRC5 and CCND1 expression and promotes cancer progression in hepatocellular carcinoma

BackgroundOCT4 and BIRC5 are preferentially expressed in human cancer cells and mediate cancer cell survival and tumor maintenance. However, the molecular mechanism that regulates OCT4 and BIRC5 expression is not well characterized.MethodsBy manipulating OCT4 and BIRC5 expression in hepatocellular carcinoma (HCC) cell lines, the regulatory mechanism of OCT4 on BIRC5 and CCND1 were investigated.ResultsIncreasing or decreasing OCT4 expression could enhance or suppress BIRC5 expression, respectively, by regulating the activity of BIRC5 promoter. Because there is no binding site for OCT4 within BIRC5 promoter, the effect of OCT4 on BIRC5 promoter is indirect. An octamer motif for OCT4 in the CCND1 promoter has directly and partly participated in the regulation of CCND1 promoter activity, suggesting that OCT4 also could upregulated the expression of CCND1. Co-suppression of OCT4 and BIRC5 induced cancer cell apoptosis and cell cycle arrest, thereby efficiently inhibiting the proliferative activity of cancer cells and suppressing the growth of HCC xenogrfts in nude mice.ConclusionOCT4 can upregulate BIRC5 and CCND1 expression by increasing their promoter activity. These factors collusively promotes HCC cell proliferation, and co-suppression of OCT4 and BIRC5 is potentially beneficial for HCC treatment.

Differentiation of Pancreatic Cancer and Chronic Pancreatitis Using Computer-Aided Diagnosis of Endoscopic Ultrasound (EUS) Images: A Diagnostic Test

Background Differentiating pancreatic cancer (PC) from normal tissue by computer-aided diagnosis of EUS images were quite useful. The current study was designed to investigate the feasibility of using computer-aided diagnostic (CAD) techniques to extract EUS image parameters for the differential diagnosis of PC and chronic pancreatitis (CP). Methodology/Principal Findings This study recruited 262 patients with PC and 126 patients with CP. Typical EUS images were selected from the sample sets. Texture features were extracted from the region of interest using computer-based techniques. Then the distance between class algorithm and sequential forward selection (SFS) algorithm were used for a better combination of features; and, later, a support vector machine (SVM) predictive model was built, trained, and validated. Overall, 105 features of 9 categories were extracted from the EUS images for pattern classification. Of these features, the 16 were selected as a better combination of features. Then, SVM predictive model was built and trained. The total cases were randomly divided into a training set and a testing set. The training set was used to train the SVM, and the testing set was used to evaluate the performance of the SVM. After 200 trials of randomised experiments, the average accuracy, sensitivity, specificity, the positive and negative predictive values of pancreatic cancer were 94.2±0.1749%,96.25±0.4460%, 93.38±0.2076%, 92.21±0.4249% and 96.68±0.1471%, respectively. Conclusions/Significance Digital image processing and computer-aided EUS image differentiation technologies are highly accurate and non-invasive. This technology provides a kind of new and valuable diagnostic tool for the clinical determination of PC.

Kaempferol inhibits cell proliferation and glycolysis in esophagus squamous cell carcinoma via targeting EGFR signaling pathway.

Antitumor activity of kaempferol has been studied in various tumor types, but its potency in esophagus squamous cell carcinoma is rarely known. Here, we reported the activity of kaempferol against esophagus squamous cell carcinoma as well as its antitumor mechanisms. Results of cell proliferation and colony formation assay showed that kaempferol substantially inhibited tumor cell proliferation and clone formation in vitro. Flow cytometric analysis demonstrated that tumor cells were induced G0/G1 phase arrest after kaempferol treatment, and the expression of protein involved in cell cycle regulation was dramatically changed. Except the potency on cell proliferation, we also discovered that kaempferol had a significant inhibitory effect against tumor glycolysis. With the downregulation of hexokinase-2, glucose uptake and lactate production in tumor cells were dramatically declined. Mechanism studies revealed kaempferol had a direct effect on epidermal growth factor receptor (EGFR) activity, and along with the inhibition of EGFR, its downstream signaling pathways were also markedly suppressed. Further investigations found that exogenous overexpression of EGFR in tumor cells substantially attenuated glycolysis suppression induced by kaempferol, which implied that EGFR also played an important role in kaempferol-mediated glycolysis inhibition. Finally, the antitumor activity of kaempferol was validated in xenograft model and kaempferol prominently restrained tumor growth in vivo. Meanwhile, dramatic decrease of EGFR activity and hexokinase-2 expression were observed in kaempferol-treated tumor tissue, which confirmed these findings in vitro. Briefly, these studies suggested that kaempferol, or its analogues, may serve as effective candidates for esophagus squamous cell carcinoma management.

Transcriptional factor OCT4 promotes esophageal cancer metastasis by inducing epithelial-mesenchymal transition through VEGF-C/VEGFR-3 signaling pathway

The octamer-binding transcription factor 4 (OCT4) can promote cancer proliferation and metastasis. Esophageal carcinoma (ECC) harbors different quantities of OCT4-positive cancer cells. These cells are highly malignant and prone to metastasis; however, the mechanism remains unknown. In this study, we found that OCT4 enhances vascular endothelial growth factor C (VEGF-C) promoter activity to promote VEGF-C expression and activates VEGF receptor 3 (VEGFR-3) in ECC cells, thereby inducing cancer cell epithelial-mesenchymal transition (EMT). Studies using xenograft models showed that OCT4 promoted xenograft growth and intraperitoneal implantation metastasis of ECC cells. Downregulation of OCT4 expression could inhibit cancer metastasis. OCT4- and VEGF-C-positive ECC presented more malignant biological behaviors and the corresponding patients exhibited a poor prognosis. The study confirmed that the OCT4/VEGF-C/VEGFR-3/EMT signaling plays a role in the progression of ECC. Understanding of how OCT4 regulates EMT and how ECC metastasis occurs will provide useful targets for the biological treatment of ECC.The octamer-binding transcription factor 4 (OCT4) can promote cancer proliferation and metastasis. Esophageal carcinoma (ECC) harbors different quantities of OCT4-positive cancer cells. These cells are highly malignant and prone to metastasis; however, the mechanism remains unknown. In this study, we found that OCT4 enhances vascular endothelial growth factor C (VEGF-C) promoter activity to promote VEGF-C expression and activates VEGF receptor 3 (VEGFR-3) in ECC cells, thereby inducing cancer cell epithelial-mesenchymal transition (EMT). Studies using xenograft models showed that OCT4 promoted xenograft growth and intraperitoneal implantation metastasis of ECC cells. Downregulation of OCT4 expression could inhibit cancer metastasis. OCT4- and VEGF-C-positive ECC presented more malignant biological behaviors and the corresponding patients exhibited a poor prognosis. The study confirmed that the OCT4/VEGF-C/VEGFR-3/EMT signaling plays a role in the progression of ECC. Understanding of how OCT4 regulates EMT and how ECC metastasis occurs will provide useful targets for the biological treatment of ECC.

Prognostic value of association of OCT4 with LEF1 expression in esophageal squamous cell carcinoma and their impact on epithelial‐mesenchymal transition, invasion, and migration

Esophageal squamous cell carcinoma (ESCC) is a malignant disease with poor prognosis. Because of early metastasis prior to diagnosis and therapeutic resistance, ESCC has become one of the leading causes of cancer‐related death. Here, we investigated the clinicopathological significance of the association of octamer‐binding transcription factor 4 (OCT4) with lymphoid enhancer‐binding factor 1 (LEF1) expression and the potential molecular mechanism in the epithelial‐mesenchymal transition (EMT), invasion, and migration of ESCC. The expression of OCT4 and LEF1 was detected via immunohistochemistry analysis. High levels of LEF1 expression were observed in 95 ESCC specimens and were obviously associated with aberrant clinicopathological features and poor patient prognosis. Our previous study showed that OCT4 expression level is elevated in ESCC, and statistical analysis showed that the elevated expression of OCT4 and LEF1 in ESCC was significantly associated with histologic grade, lymph node metastasis, TNM stage, and poor patient prognosis. The specific inhibition of OCT4 expression via a lentivirus encoding OCT4‐shRNA (LV‐shOCT4) in Eca109 cells led to decreased levels of OCT4 and LEF1 in vitro. Additionally, we applied a rescue strategy by infecting LV‐shOCT4 Eca109 cells with a LEF1 overexpression plasmid (p‐LEF1) and detected changes in EMT, migration, and invasion. Unsurprisingly, the p‐LEF1 group exhibited greater EMT, invasion, and migration than did the LV‐shOCT4 and negative control groups. This study demonstrates for the first time the relationship between OCT4 and LEF1 expression. The combination of high expression of OCT4 and LEF1 was associated with clinicopathological features of atypical patients, and this combination might be an ideal prognostic factor in ESCC. OCT4 positively regulated LEF1 expression, and LEF1 mediated the effects of OCT4 in cancer cell EMT, invasion, and migration. The data presented here suggest that the inhibition of OCT4‐LEF1 signaling may be a new therapeutic target for the treatment of ESCC.