Aqueous Extract of Guava (Psidium guajava L.) Leaf Ameliorates Hyperglycemia by Promoting Hepatic Glycogen Synthesis and Modulating Gut Microbiota.

Type 2 diabetes mellitus (T2DM) is a major global health concern. Psidium guajava L. (guava) is widely used for food as well as a folk medicine. Previous studies have shown its anti-diabetic and anti-inflammatory properties. However, the underlying mechanisms remains to be elusive. In this study, we assessed the potential therapeutic effects of aqueous extract of guava leaves (GvAEx) on T2DM and explored their potential mechanisms in vivo and in vitro. GvAEx was gavage administered for 12 weeks in diabetic db/db mice. Our results have demonstrated that GvAEx significantly lowered fasting plasma glucose levels (p < 0.01) and improved glucose tolerance and insulin sensitivity (p < 0.01, p < 0.05, respectively). Additionally, GvAEx increased hepatic glycogen accumulation, glucose uptake and decreased the mRNA expression levels of gluconeogenic genes. Furthermore, GvAEx-treatment caused higher glucose transporter 2 (GLUT2) expression in the membrane in hepatocytes. Notably, for the first time, we have elaborated the possible mechanism of the hypoglycemic effect of GvAEx from the perspective of intestinal microbiota. GvAEx has significantly changed the composition of microbiota and increased short chain fatty acid (SCFA) -producing Lachnospiraceae family and Akkermansia genus in the gut. Taken together, GvAEx could alleviate hyperglycemia and insulin resistance of T2DM by regulating glucose metabolism in the liver and restoring the gut microbiota. Thus, GvAEx has the potential for drug development against T2DM.

Convergent genomic signatures of high-altitude adaptation among domestic mammals.

Abundant and diverse domestic mammals living on the Tibetan Plateau provide useful materials for investigating adaptive evolution and genetic convergence. Here, we used 327 genomes from horses, sheep, goats, cattle, pigs and dogs living at both high and low altitudes, including 73 genomes generated for this study, to disentangle the genetic mechanisms underlying local adaptation of domestic mammals. Although molecular convergence is comparatively rare at the DNA sequence level, we found convergent signature of positive selection at the gene level, particularly the EPAS1 gene in these Tibetan domestic mammals. We also reported a potential function in response to hypoxia for the gene C10orf67, which underwent positive selection in three of the domestic mammals. Our data provide an insight into adaptive evolution of high-altitude domestic mammals, and should facilitate the search for additional novel genes involved in the hypoxia response pathway.

Elevated expression of IRS-1 associates with phosphorylated Akt expression and predicts poor prognosis of breast invasive ductal carcinoma.

Overexpression of insulin receptor substrate 1 (IRS-1) has been reported to promote cell growth, atypical hyperplasia, and carcinogenesis, and phosphorylated Akt (p-Akt) is certified to be involved in many types of cancers such as breast invasive ductal carcinoma (BIDC). However, the relationship between IRS-1 and Akt, as well as the role of expression of IRS-1 in BIDC, has never been reported. The purpose of this research is to investigate the association between expression of IRS-1 and p-Akt proteins and clinicopathological features of BIDC by immunohistochemistry, as well as the survival status. The results showed that the percentage of either elevated expression of IRS-1 or positive p-Akt expression in BIDC was significantly higher than that in control breast tissue from noncancer patients (P < .001 and P = .001, respectively). Overexpression of IRS-1 was evidently associated with positive expression of p-Akt (r = 0.337, P < .001). Also, positive percentage of p-Akt expression was statistically different among different molecular subtypes of BIDC (highest in luminal B BIDC, P = .009). Furthermore, significantly worse overall survival was found in BIDC patients with high expression of IRS-1 and p-Akt than in patients with low expression (P = .006 and P = .004, respectively). The multivariate Cox proportional hazard regression analysis showed that high expression of IRS-1 and positive expression of p-Akt protein were independent poor prognostic factors for patients with BIDC (P = .022 and P = .046, respectively). In conclusion, we report for the first time that overexpression of IRS-1 protein is associated with expression of p-Akt, and overexpression of IRS-1 and positive expression of p-Akt might be independent biomarkers for poor prognosis in BIDC.

Suppression Of ß-catenin Nuclear Translocation By CGP57380 Decelerates Poor Progression And Potentiates Radiation-Induced Apoptosis in Nasopharyngeal Carcinoma.

Nuclear localization of ß-catenin is essential for the progression of various human cancers via transcriptional upregulation of downstream genes. The MAP kinase interacting serine/threonine kinase (MNK)-eukaryotic translation initiation factor 4E (eIF4E) axis has been reported to activate Wnt/ß-catenin signaling, and CGP57380, an inhibitor of MNK kinases, inhibits the proliferation of multiple cancers. In this study, we showed that ß-catenin signaling (including ß-catenin, cyclin D1, c-Myc, and MMP-7) and p-eIF4E expression were elevated in nasopharyngeal carcinoma (NPC) compared with non-cancerous nasopharyngeal epithelial tissues, and was associated with clinical characteristics of NPC patients. Lymph node metastasis, gender, aberrant ß-catenin expression, and elevated levels of MMP-7 and cyclin D1 were independent prognostic factors. Significantly, expression of p-eIF4E was positively correlated with ß-catenin, and targeting the MNK-eIF4E axis with CGP57380 downregulated ß-catenin in the nucleus, which in turn decreased proliferation, cell cycle progression, migration, invasion, and metastasis of NPC in vitro and in vivo. CGP57380 also potentiated radiation-induced apoptosis in NPC. Moreover, CGP57380 upregulated ß-catenin in the cytoplasm thus blocking epithelial-mesenchymal transition (EMT), a key mechanism in cancer cell invasiveness and metastasis. Mechanistically, inhibition of ß-catenin nuclear translocation by CGP57380 was dependent on AKT activation. Notably, identification of the MNK/eIF4E/ß-catenin axis might provide a potential target for overcoming the poor prognosis mediated by ß-catenin in NPC.

Increased expression of Cks1 protein is associated with lymph node metastasis and poor prognosis in nasopharyngeal carcinoma.

BACKGROUND: The Cks1 protein is an essential factor in regulating cell cycle by mediating the ubiquitination of CDK inhibitor p27kip1. It has been reported that aberrant expression of Cks1 and p27kip1 proteins was found in various tumors and related to initiation and progression of carcinomas. However, the potential roles which Cks1 and p27KIP1 proteins play in NPC remain unclear. This study aims to examine the expression status of Cks1 and p27kip1 and their possible prognostic significance in NPC. METHODS: Paraffin-embedded specimens with NPC (n = 168) and non-tumor nasopharyngeal tissues (n = 49) were analyzed by IHC. RESULTS: Expression of Cks1 increased in NPC tissues compared with non-tumor nasopharyngeal tissues (P < 0.05), whereas p27kip1 protein frequently expressed in non-tumor nasopharyngeal tissues compared with NPC tissues (P < 0.05). There was a significant reverse correlation between Cks1 and p27kip1 protein expression in NPC (r = -0.189, P < 0.05).In addition, Kaplan-Meier survival curve showed that there was a significant tendency of shorter overall survival (OS) in NPC patients with Cks1 positive expression compared to negative ones, especially in patients with lymph node metastasis (P < 0.001, respectively). But there was no significance between p27kip1 expression and survival viability of NPC patients. Multivariate Cox regression analysis further identified increased expression of Cks1 was the independent poor prognostic factor for NPC (p = 0.13). CONCLUSION: Our research found expression of Cks1 increased and was inverse to the expression of p27KIP1. High expression of Cks1 was significantly associated with lymph node metastasis and survival status in NPC. In addition, the abnormally high level of Cks1 protein was proved to be an independent poor prognostic factor in NPC. These results may provide novel clue for NPC therapy method.

High expression of heat shock protein 10 (Hsp10) is associated with poor prognosis in oral squamous cell carcinoma.

Heat shock protein 10 (Hsp10), located in mitochondria, is a co-chaperone involved in the protein folding and aggregation with Hsp60. Besides, a wide range of other extramitochondrial and extracellular activities, such a mammalian mitochondrial chaperonin including modulation of apoptosis, inflammation, and carcinogenesis, have been reported. Expression of Hsp10 protein in oral squamous cell carcinomas (OSCC) and the non-cancerous squamous epithelium was detected using immunohistochemistry we retrospectively evaluated the correlations between Hsp10 expression and the clinicopathological characteristics of OSCC. Our results showed that percentage of high expression of Hsp10 in the OSCC was statistically higher than that in the non-cancerous squamous epithelium (P = 0.006). What is more, high Hsp10 expression was significantly associated with shorter overall survival in patients with OSCC (P<0.001). In addition, our results identified that the high expression of Hsp10 was significantly correlated with OSCC patients age, the history of chewing betel nut, pathological grade, lymph node metastasis and radiotherapy after operation (P = 0.008, P = 0.021, P = 0.026, P = 0.008, P = 0.049 respectively). Multivariate Cox regression analysis further identified that high expression of Hsp10 protein was an independent poor prognostic factor for OSCC (P<0.001). High Hsp10 expression might play important roles in the progression of OSCC, and it might act as a novel valuable independent biomarker to predict poor prognosis in patients with OSCC.

Primary synovial sarcoma of the larynx in a 14-year-old boy diagnosed by immunohistochemistry and fluorescence in situ hybridization: a rare case report.

Synovial sarcoma (SS) is an aggressive soft tissue tumor, which occurs predominantly in young adults. The SS can arise in almost any part of the body, especially in the lower extremity. The SS of head and neck accounts for 1.9-3.5% of all SS, however, the mass appears very extremely rare in the larynx. We report a case of a biphasic SS in the larynx. A 14-year-old boy appeared without apparent inducement with hoarseness, dyspnea, fever, cough, hemoptysis, pharyngeal foreign body sensation, dysphagia, odynophagia and other symptoms since nearly one month ago. The patient underwent partial laryngectomy and performed a wide surgical excision of the tumor with a free margin. Pathological examinations of the tumor specimen revealed an encapsulated and firm tumor lesion. The grayish-white to dark-brown mass was 8×6×4 cm, arising from the left of aryepiglottic fold. Histological examination showed the characteristic histomorphological features such as biphasic pattern of short spindle cells and epithelioid cells, including glandular differentiation. Immunohistochemically, staining for vimentin, bcl-2 and calponin were typically positive in the spindle tumor cells. Staining for CK was typically positive in the epithelioidtumor cells. Staining for EMA, CD99 and TLE-1 were typically positive in both the epithelioid and spindle tumor cells. The presence of SYT-SSX fusion gene from chromosomal translocation was detected by FISH in this case. Two months postoperatively, the patient received local radiotherapy. Combined treatment may be effective and the patient is alive without tumor recurrence in radiological and clinical examination after 18 months of follow-up.

High expression of heat shock protein 10 correlates negatively with estrogen/progesterone receptor status and predicts poor prognosis in invasive ductal breast carcinoma.

Heat shock proteins (HSPs) usually are associated with stress response and tolerance. HSP10 is a co-chaperone for HSP60, which is involved in the mitochondrial protein-folding machinery. To the best of our knowledge, the expression of HSP10 in invasive ductal breast carcinoma (IDBC) has never been reported. In the present study, HSP10 expression in 242 cases of IDBC and 46 cases of noncancerous breast tissues was detected by immunohistochemistry staining. High expression was significantly more common in IDBC than in noncancerous breast tissues (P<.001). Also, high expression was significantly more common in poorly differentiated than in well- and moderately differentiated IDBC (P=.023). Furthermore, high expression correlated negatively with estrogen receptor and progesterone receptor expression (P=.031 and P=.042, respectively). The most interesting result of the study was that high expression of HSP10 was significantly associated with shorter overall survival by both univariate and multivariate analyses (P=.013 and P=.036, respectively). In conclusion, we report for the first time that high expression of HSP10 is negatively associated with estrogen receptor/progesterone receptor status and might be a novel independent biomarker for poor prognosis in IDBC.

Elevated levels of p-Mnk1, p-eIF4E and p-p70S6K proteins are associated with tumor recurrence and poor prognosis in astrocytomas.

Malignant astrocytomas are able to invade neighboring and distant areas of the normal brain. Signaling pathway alterations play important role in the development of astrocytomas. Deregulation of eukaryotic translation initiation factor 4E (eIF4E) by MAP kinase-interacting kinases (Mnk) on Ser-209 directly or PI3K/mTOR/S6K pathway indirectly has a critical effect on promoting cellular proliferation, malignant transformation and metastasis. We examined and analyzed the correlation between expression of p-Mnk1, p-eIF4E and p-p70S6K proteins and clinicopathological features in 103 astrocytomas and 54 non-tumorous brain tissues. The results indicated that positive percentage of overexpression of p-Mnk1 and p-eIF4E proteins in astrocytomas were significantly higher than that of in the non-tumorous brain tissues (P < 0.05). Elevated p-Mnk1 and p-eIF4E and co-overexpressed three proteins were associated with tumor recurrence (P = 0.003, P = 0.006, P = 0.007, respectively). Overexpressed p-eIF4E significantly correlated with the tumor size (P = 0.019). In addition, overexpression of p-eIF4E and three proteins common expression were related to the WHO grade of astrocytomas (P = 0.001, P = 0.044 respectively). Spearman's rank correlation test further showed that the expression of p-Mnk1 was strongly positive correlated with the expression of p-eIF4E in astrocytomas (r = 0.294, P = 0.003). Besides, overexpression of p-eIF4E and co-expression of p-Mnk1, p-eIF4E and p-p70S6K proteins were inversely correlated with overall survival rates of astrocytomas. Multivariate Cox regression analysis further identified that the elevated p-eIF4E expression, three proteins common expression were correlated with unfavorable prognosis of astrocytomas regardless of ages and WHO grades. Taken together, overexpression of p-eIF4E and co-expression of p-Mnk1, p-eIF4E and p-p70S6K proteins could be used as novel independent poor prognostic biomarkers for patients with astrocytomas.

CD74 interacts with CD44 and enhances tumorigenesis and metastasis via RHOA-mediated cofilin phosphorylation in human breast cancer cells.

CD74, also known as Ii, was initially considered to participate primarily in antigen presentation. Subsequent studies have shown that CD74 is highly expressed in various types of tumor cells and has multiple roles in a variety of biological processes. CD74 is thought to promote breast cancer metastasis, but the molecular mechanism remains elusive. In the present study, our results showed that CD74 was more highly expressed on the membrane and in the cytoplasm of breast cancer tissues than in control breast tissues. Consistently, CD74 downregulation reduced MDA-MB-231 cell invasion and migration and suppressed protrusions in breast cancer cells. Moreover, CD74 overexpression promoted the phosphorylation of the actin-severing protein cofilin (CFL1), resulting in actin polymerization in breast cancer cells. CD44 was required for the up-regulation of CFL1 phosphorylation by CD74 because CD44 knockdown downregulated CD74-induced CFL1 phosphorylation, while CD74 overexpression could not rescue CFL1 phosphorylation. Moreover, RHOA is necessary for CFL1 phosphorylation and cell migration induced by CD74 in breast cancer cells. Our findings highlight the critical role of CD74 in breast cancer metastasis. New drugs and antibodies targeting CD74 may be effective strategies for breast cancer therapy.

CGP57380 enhances efficacy of RAD001 in non-small cell lung cancer through abrogating mTOR inhibition-induced phosphorylation of eIF4E and activating mitochondrial apoptotic pathway.

The mammalian target of rapamycin (mTOR) is a potentially important therapeutic target in a broad range of cancer types. mTOR inhibitors such as rapamycin and its analogs (rapalogs) have been proven effective as anticancer agents in non-small cell lung cancer (NSCLC), whereas they strongly enhance phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) and activation of Akt, which cause resistance to mTOR-targeted therapy after an initial response. Rapamycin induces eIF4E phosphorylation by activating MAPK-interacting kinases (Mnks), and therefore targeting Mnk/eIF4E pathway represents a potential therapeutic strategy for the treatment of NSCLC. Here, our results showed that over-expression of p-Mnk1 and p-eIF4E was significantly associated with poor overall survival of NSCLC patients and high expression of p-Mnk1 might act as an independent prognostic biomarker for these patients. Meanwhile, inhibiting Mnk1 expression by Mnk inhibitor (CGP57380) could abrogate rapalogs (RAD001)-induced eIF4E phosphorylation and Akt activation. Furthermore, combination of CGP57380 and RAD001 could induce NSCLC cells apoptosis via activating intrinsic mitochondrial pathway, and exert synergistic antitumor efficacy both in vitro and in vivo. In conclusion, combination of targeting both mTOR and Mnk/eIF4E signaling pathways to enhance effectiveness of mTOR-targeted cancer therapy might be significant innovation for the personalized treatment of NSCLC.

4EGI-1 induces apoptosis and enhances radiotherapy sensitivity in nasopharyngeal carcinoma cells via DR5 induction on 4E-BP1 dephosphorylation.

The eIF4F complex regulated by a various group of eIF4E-binding proteins (4E-BPs) can initial the protein synthesis. Small molecule compound 4EGI-1, an inhibitor of the cap-dependent translation initiation through disturbing the interaction between eIF4E and eIF4G which are main elements of the eIF4E complex, has been reported to suppress cell proliferation by inducing apoptosis in many types of cancer. And death receptor 5 (DR5) is a major component in the extrinsic apoptotic pathway. However, the correlation among 4EGI-1, DR5 and 4E-BPs have not been discovered in NPC now. Therefore, we intend to find out the effect of 4EGI-1 on the apoptosis process of NPC and the relationship among 4EGI-1, DR5 and 4E-BPs. Our results revealed a significant down regulation of DR5 expression in NPC tissues, which inversely correlated with lymph node metastasis status and clinical stages. Depressed DR5 expression was an independent biomarker for poor prognosis in NPC, and elevated DR5 expression showed longer overall survival time in 174 NPC patients. Besides, 4EGI-1 induced apoptosis in NPC cells through the DR5-caspase-8 axis on 4E-BP1 and eIF4E dephosphorylation exerting positive influence on their anti-tumor activities. The induction of DR5 also sensitized NPC cells to radiotherapy, and the SER was 1.195. These results establish the death receptor pathway as a novel anticancer mechanism of eIF4E/eIF4G interaction inhibitor in NPC.

Lipoadenoma of the adrenal gland: report of a rare entity and review of literature.

Adrenal lipoadenoma is an extremely rare tumor. Only four cases have been reported so far. The authors reported a case of adrenal lipoadenoma in a 46-year-old man with the history of abdominal pain. The present case, manifesting as a nonfunctional adrenal tumor, is characteristically comprised of a mixture of mature adipocytes and adrenocortical cells. We also reviewed this tumor in different organs which have been published in the literature.

FLOT-2 is an independent prognostic marker in oral squamous cell carcinoma.

Flotillin-2 (Flot-2) is an important component of cellular membrane, which involves in various cellular processes and recent studies have revealed that Flot-2 played important roles in cancer progression. The expression and prognostic impact of Flot-2 in oral squamous cell carcinoma (OSCC) have not been well studied. So, a tissue microarray (TMA) based on immunohistochemical analysis of surgical resection of tumor tissues of 78 cases of OSCC patients and 27 cases of adjacent non-cancerous squamous epithelium tissues was conducted. This study focused on detecting Flot-2 expression and analyzing its prognostic impact on OSCC. The result showed that the positive percentage of Flot-2 expression in OSCC (74.4%, 58/78) was significantly higher than that in adjacent non-cancerous squamous epithelium tissues (25.9%, 7/27) (P<0.001). Additionally, the positive expression of Flot-2 in OSCC patients with a history of alcohol consumption was significantly higher than those nonusers (P=0.027). Both univariate and multivariate survival analysis indicated that increased expression Flot-2 protein was significantly correlated inversely with overall survival rates in OSCC patients (P=0.046, P=0.002). Taken together, positive expression of Flot-2 protein may be an independent biomarker for poor prognosis in OSCC.

Flot-2 Expression Correlates with EGFR Levels and Poor Prognosis in Surgically Resected Non-Small Cell Lung Cancer.

We previously reported that expression of Flotillin 2 (Flot-2), a protein isolated from caveolae/lipid raft domains, increased significantly in nasopharyngeal carcinoma (NPC) compared with normal tissues. Signal transduction through epidermal growth factor receptors (EGFR) and Flot-2 play an important role in cancer development, but their precise role in lung cancer has not been investigated. In this study, we have investigated the correlation between the expression of Flot-2 and EGFR, which increase significantly in non-small cell lung cancer (NSCLC) patients (n=352) compared with non-cancer tissues. Additionally, patients with advanced stages of NSCLC had higher positive expression of Flot-2 and EGFR than patients with early stages. NSCLC patients with increased expression of Flot-2 and EGFR had significantly less overall survival rates than patients with less expression of Flot-2 and EGFR. Taken together, our data suggest that increased expression of Flot-2 and EGFR in NSCLC patients is inversely proportional to the disease prognosis and that increased expression of Flot-2 associated with increased EGFR may serve as a biomarker to predict poor disease prognosis.

Increased expression of IRS-1 is associated with lymph node metastasis in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a head and neck malignant tumor rare throughout most of the world but common in Southeast Asia, especially in Southern China, which is with characteristics of early cervical lymph node metastasis and high incidence rate of distant metastasis. Insulin receptor substrate 1 (IRS-1) is a signaling adapter protein that is encoded by the IRS-1 gene in humans, plays an important role in the development, progression, invasion and metastasis of tumors. The aim of the present study was to investigate the association between the expression of IRS-1 protein and clinicopathological characteristics in NPC by immunohistochemistry. The results showed that the expression level of IRS-1 was significant higher in NPC than that in the control nasopharyngeal epithelia (P = 0.042). The positive percentage of IRS-1 expression in NPC with lymph node metastasis was also significantly higher than those without lymph node metastasis (P = 0.008). Positive expression of IRS-1 was proved to be the independent predicted factor for lymph node metastasis of NPC (P = 0.025) regardless of age, gender, histological type and clinical stages by multivariate logistic regression analysis. In addition, results showed higher sensitivity and agreement rate of IRS-1 for predicting lymph node metastasis of NPC patients. Taken together, high expression of IRS-1 might be closely correlated with lymph node metastasis in NPC and positive expression of IRS-1 could be used as an independent biomarker for predicting lymph node metastasis of NPC.

Fatty acid synthase-associated protein with death domain: a prognostic factor for survival in patients with nasopharyngeal carcinoma.

Fatty acid synthase-associated protein with death domain (FADD) is a key adaptor protein that bridges a death receptor (eg, death receptor 5) to caspase 8 to form the death-inducing signaling complex during apoptosis. The expression and prognostic impact of FADD in nasopharyngeal carcinoma (NPC) have not been well studied. This study focused on detecting FADD expression and analyzing its prognostic impact on NPC. FADD expression was assessed on pretreatment tumor tissues of 248 cases of NPC patients and 76 cases of noncancerous nasopharyngeal control tissue. The results showed that the positive percentage of FADD expression in NPC (63.7%, 158/248) was significantly higher than that in the noncancerous nasopharyngeal control tissues (28.9%, 22/76) (P < .0001). The positive expression of FADD in the NPC with cervical lymph node metastasis was significantly higher than those without lymph node metastasis (P = .009). Furthermore, FADD expression was more pronouncedly increased in metastatic NPC than the matched primary NPC tissues (P = .017). Both univariate and multivariate survival analysis indicated that increased FADD expression was significantly correlated inversely with overall survival in NPC patients (P = .003 and P = .007, respectively). Taken together, high expression of FADD may be an independent biomarker for poor prognosis in NPC.

Activation of Akt/mTOR pathway is associated with poor prognosis of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a malignant tumor of the head and neck region, which frequently occurs in Southeast Asia, especially in the south of China. It is known that the mammalian target of rapamycin (mTOR) pathway plays a central role in regulating cellular functions, including proliferation, growth, survival, mobility, and angiogenesis. Aberrant expression of the mTOR signaling pathway molecules has been found in many types of cancer. However, whether the alterations of p-Akt, p-p70S6K and p-4EBP1 protein expression are associated with clinicopathological features and prognostic implications in NPC have not been reported. The purposes of the present study are to investigate the association between the expression of p-Akt, p-p70S6K and p-4EBP1 proteins and clinicopathological features in NPC by immunohistochemistry. The results showed that the positive percentage of p-Akt, p-p70S6K and p-4EBP1 proteins expression in NPC (47.2%, 73.0% and 61.7%, respectively) was significantly higher than that in the non-cancerous nasopharyngeal control tissue (33.3%, 59.1% and 47.0%, respectively). There was a significantly higher positive expression of p-Akt in undifferentiated non-keratinizing nasopharyngeal carcinoma than that in differentiated non-keratinizing nasopharyngeal carcinoma (P = 0.014). Additionally, positive expression of p-p70S6K and p-4EBP1 proteins, and positive expression of either of p-Akt, p-p70S6K and p-4EBP1 were significantly correlated inversely with overall survival rates of NPC patients (P = 0.023, P = 0.033, P = 0.008, respectively). Spearman's rank correlation test showed that expression of p-Akt in NPC was significantly associated with expression of p-p70S6K (r = 0.263, P<0.001) and p-4EBP1(r = 0.284, P<0.001). Also there was an obviously positive association between expression of p-p70S6K and p-4EBP1 proteins in NPC (r = 0.286, P<0.001). Multivariate Cox regression analysis further identified positive expression of p-4EBP1 and p-p70S6K proteins were the independent poor prognostic factors for NPC (P = 0.043, P = 0.027, respectively). Taken together, high expression of p-p70S6K and p-4EBP1 proteins may act as valuable independent biomarkers to predict a poor prognosis of NPC.

Increased expression of flotillin-2 protein as a novel biomarker for lymph node metastasis in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a head and neck malignant tumor rare throughout most of the world but common in Southeast Asia, especially in Southern China. Flotillin-2 (Flot-2) is not only an important component of cellular membrane, but also involves in various cellular processes such as membrane trafficking, T cell and B cell activation, regulation of several signaling pathways associated with cell growth and malignant transformation, keeping structure and junction of epidermal cells and formation of filopodia. Although such molecular effects of Flot-2 have been reported, whether the expression of Flot-2 protein is associated with clinicopathologic implication for NPC has not been reported. The purpose of this research is to investigate the expression of Flot-2 protein in NPC and control nasopharyngeal epithelial tissues by immunohistochemistry and elucidate the association between the expression of Flot-2 protein and clinicopathological characteristics of NPC. The results showed that the positive percentage of Flot-2 expression in the NPC, nasopharyngeal epithelia with atypical hyperplasia and in the control nasopharyngeal mucosa epithelia was 88.8% (119/134), 76.9% (10/13) and 5.7% (5/88), respectively. There was significantly higher expression of Flot-2 protein in NPC and nasopharyngeal epithelia with atypical hyperplasia compared to the control nasopharyngeal mucosa epithelia (P<0.001, respectively). The positive percentage of Flot-2 protein expression in NPC patients with lymph node metastasis was significantly higher than those without lymph node metastasis. Increasing of Flot-2 expression was obviously correlated with clinical stages of NPC patients. The expression of Flot-2 was proved to be the independent predicted factor for lymph node metastasis by multivariate analysis. The sensitivity of Flot-2 for predicting lymph node metastasis of NPC patients was 93%. Taken together, our results suggest that the increased expression of Flot-2 protein is a novel higher sensitivity biomarker that can predict lymph node metastases in NPC.