PTEN (phosphatase and tensin homolog), a tumor suppressor frequently mutated in human cancer, has various cytoplasmic and nuclear functions. PTEN translocates to the nucleus from the cytoplasm in response to oxidative stress. However, the mechanism and function of the translocation are not completely understood. In this study, topotecan (TPT), a topoisomerase I inhibitor, and cisplatin (CDDP) were employed to induce DNA damage. The results indicate that TPT or CDDP activates ATM (ATM serine/threonine kinase), which phosphorylates PTEN at serine 113 and further regulates PTEN nuclear translocation in A549 and HeLa cells. After nuclear translocation, PTEN induces autophagy, in association with the activation of the p-JUN-SESN2/AMPK pathway, in response to TPT. These results identify PTEN phosphorylation by ATM as essential for PTEN nuclear translocation and the subsequent induction of autophagy in response to DNA damage.
GINS complex subunit 2 (GINS2), a member of the GINS complex, is involved in DNA replication. GINS2 is upregulated in a variety of aggressive tumors. However, its role in cervical cancer carcinogenesis remains to be elucidated. We investigated the clinical significance of GINS2 in patients with early-stage cervical cancer and its biological functions in cervical cancer progression. GINS2 expression was analyzed in cervical cancer cell lines and in 8 matched cervical cancer samples at the mRNA and protein levels using real-time PCR and western blotting, respectively. GINS2 protein expression in 155 paraffin-embedded cervical cancer specimens was validated using immunohistochemistry. Statistical analysis was used to evaluate its clinicopathological significance. Short hairpin RNA interference, anchorage-independent growth ability, colony formation assay, wound healing ability, Transwell assays and western blotting were used to determine the effects of GINS2 on the aggressive phenotype of cervical cancer cells. There was obvious upregulation of GINS2 in the cervical cancer cell lines and tumor specimens compared to that in the normal cervical tissues. Significant correlations were identified between GINS2 expression and squamous cell carcinoma antigen (SCC-Ag; P<0.001), deep stromal invasion (P=0.021), vital status (P<0.001), recurrence (P<0.001) and pelvic lymph node metastasis (PLNM; P<0.001). Moreover, patients with higher GINS2 expression had shorter overall survival (OS) compared to patients with low GINS2 expression. Multivariate analysis revealed that GINS2 may serve as an independent risk factor of poor prognosis in early-stage cervical cancer. In addition, GINS2 downregulation markedly suppressed cell proliferation and tumorigenic ability, as well as cell migration and invasion. Our findings suggest that GINS2 is a novel indicator of PLNM and a valuable prognostic biomarker in early-stage cervical cancer, and subsequently is a valuable molecular target for cervical cancer diagnosis and treatment.
The serine ⁄ threonine kinase UNC-51-like kinase 1 (ULK1) plays an essential role in autophagosome formation, although the exact molecular mechanism is unknown. The present study was first to investigate the clinical and prognostic significance of ULK1 in esophageal squamous cell carcinoma (ESCC). Protein and mRNA levels of ULK1 in normal esophageal epithelial cells, ESCC cell lines, paired ESCC lesions and the adjacent noncancerous tissues were examined using western blot and real-time RT-PCR. The results showed that only the ULK1 protein level was upregulated in ESCC samples compared with normal esophageal cells and tissues. Also, we found that protein stabilization of ULK1 was higher in ESCC cell lines. Furthermore, immunohistochemical staining of ULK1 was performed on the tissue microarray containing 248 ESCC and 51 normal esophageal tissues. A total of 70.2% ESCC specimens showed intensive expression of ULK1 in contrast to the undetectable expression of ULK1 in normal esophageal tissues. Statistical analysis revealed that ULK1 expression was significantly correlated with T status (P = 0.048). Moreover, patients with higher ULK1 expression were associated with shorter overall survival time. Multivariate analysis suggested that ULK1 expression and N status (P < 0.001) were independent prognostic indicators for the survival of patients. Functional studies showed that suppression of ULK1 expression in ESCC cell lines by specific small interfering RNA resulted in inhibition of cell proliferation and induction of apoptosis under starvation conditions. These findings provide evidence that ULK1 represents a novel and clinically useful biomarker for ESCC patients and plays an important role during the progression of ESCC. (Cancer Sci 2011; 102: 1568-1575 E sophageal carcinoma has been reported as the eighth most occurring cancer and the sixth leading cause of cancer death in the world.(1,2) Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal carcinoma in Asia, (3) especially in north central China.(4) Great advances have been achieved in surgical techniques and perioperative management in recent years; however, the mortality of this disease has not been significantly decreased. The main reason for poor prognosis of ESCC is that most early cases are asymptomatic, therefore patients are usually diagnosed at an advanced stage when the cancer has displayed local invasion and lymph node metastasis. Currently, only the stage based on the tumornode-metastasis (TNM) classification is widely accepted as a prognostic factor, which is not as precise as desired. Therefore, there is urgency to identify sensitive and specific biological markers that could accurately evaluate the prognosis of ESCC clinically.Macroautophagy (herein referred to as autophagy) is a dynamic process that intracellular double-membrane structures called autophagosomes sequester cytoplasmic contents, then fuse with lysosomes for breakdown and turn over these metabolic materials. (5,6) In normal cells, autophagy h...
Background: The prognosis of human astrocytoma is poor, and the molecular alterations underlying its pathogenesis still needed to be elucidated. Nucleolar and spindle associated protein 1 (NUSAP1) was observed in several types of cancers, but its role in astrocytoma remained unknown. Methods:The expression of NUSAP1 in astrocytoma cell lines and tissues were measured with western blotting and Real-Time PCR. Two hundred and twenty-one astrocytoma tissue samples were analyzed by immunochemistry to demonstrate the correlation between the NUSAP1 expression and clinicopathological characteristics. 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay, colony formation, transwell matrix penetration assay, wound healing assay and anchorage-independent growth assay were used to investigate the biological effect of NUSAP1 in astrocytoma. An intracranial brain xenograft tumor model was used to confirm the oncogenic role of NUSAP1 in human astrocytoma. Luciferase reporter assay was used to investigate the effect of NUSAP1 on Hedgehog signaling pathway.Results: NUSAP1 was markedly overexpressed in astrocytoma cell lines and tissues compared with normal astrocytes and brain tissues. NUSAP1 was found to be overexpressed in 152 of 221 (68.78%) astrocytoma tissues, and was significantly correlated to poor survival. Further, ectopic expression or knockdown of NUSAP1 significantly promoted or inhibited, respectively, the invasive ability of astrocytoma cells. Moreover, intracranial xenografts of astrocytoma cells engineered to express NUSAP1 were highly invasive compared with the parental cells. With regard to its molecular mechanism, upregulation of NUSAP1 in astrocytoma cells promoted the nuclear translocation of GLI family zinc finger 1 (GLI1) and upregulated the downstream genes of the Hedgehog pathway.Conclusion: These findings indicate that NUSAP1 contributes to the progression of astrocytoma by enhancing tumor cell invasiveness via activation of the Hedgehog signaling pathway, and that NUSAP1 might be a potential prognostic biomarker as well as a target in astrocytoma.
Abstract. The objective of the present study was to investigate the therapeutic efficacy of flavonoid components in Scutellaria baicalensis on proliferation, metastasis and lung cancer-associated inflammation during nicotine induction in the A549 and H1299 lung cancer cell lines. After experimental period, augmentation of proliferation was observed, accompanied by marked decrease in apoptotic cells in nicotine-induced lung cancer cells; additionally, nicotine-exposed cells exhibited increased invasive and migratory abilities based on invasion and wound-healing assay. Flavones in Scutellaria, baicalin, baicalein and wogonin significantly counteracted the above deleterious changes. Moreover, assessment of tumor apoptotic and metastatic factors on mRNA levels by quantitative PCR and protein levels by western blotting revealed that these phytochemical treatments effectively negated nicotine-induced upregulated expression of bcl-2, bcl-2/bax ratio, caspase-3, matrix metalloproteinase (MMP)-2 and MMP-9 as well as downregulated expression of bax. Further analysis of inflammatory markers such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 in cell culture supernatant and mRNA and protein expression of nuclear transcription factor-kappaB (NF-κB) and I kappa B-alpha (IκB-α) was carried out to substantiate the anti-inflammatory effect of flavones in Scutellaria in nicotine-exposed lung cancer cells. The therapeutic effects observed in the present study are attributed to the potent potential against proliferation, metastasis and inflammatory microenvironment by flavonoid components in Scutellaria in nicotine-induced lung cancer cells.
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