Decoy receptor 3 (DcR3), a member of tumor necrosis factor receptor superfamily, has been implicated in tumorigenesis through its abilities to modulate immune responses and induce angiogenesis. Epstein-Barr virus (EBV), a ubiquitous gamma-herpesvirus, is associated with malignancies including nasopharyngeal carcinoma (NPC). Previous studies show that DcR3 is overexpressed in EBV-positive lymphomas and Rta, an EBV transcription activator, can upregulate DcR3 in Burkitt lymphoma cell lines. However, DcR3 expression has not been demonstrated in EBV-associated NPC nor have there been any EBV latent genes linked to DcR3 upregulation. Here, we showed DcR3 was overexpressed in NPC. Higher DcR3 expression score and DcR3-positive rate were found in metastatic NPC than in primary NPC tissues, suggesting DcR3 may enhance cell metastatic potential. This hypothesis is supported by our observation that NPC HONE-1 cells overexpressing DcR3 exhibited significant higher migration and invasion abilities in vitro. We found besides Rta, EBV latent membrane protein (LMP) 1 can upregulate DcR3 via nuclear factor-kappaB and phosphatidylinositol 3-kinase-signaling events. Approximate 75% of LMP1-positive NPC tissues overexpressed DcR3, suggesting LMP1 may enhance DcR3 expression in vivo. Data herein suggested that increasing DcR3 expression by LMP1 not only helps EBV-associated cancer cells gain survival advantage by preventing host immune detection but also increases the chance of cancer metastasis by enhancing cell migration and invasion. All these DcR3-mediated events facilitate normal cells to gain cancer hallmarks.
AIMTo investigate the clinicopathological significance of progesterone receptor membrane component 1 (PGRMC1) and PGRMC2 in hepatocellular carcinoma (HCC).METHODSWe performed immunohistochemical staining to evaluate the estrogen receptor (ER), progesterone receptor (PR), PGRMC1, and PGRMC2 in a clinical cohort consisting of 89 paired HCC and non-tumor liver samples. We also analyzed HCC data (n = 373) from The Cancer Genome Atlas (TCGA). We correlated the expression status of PGRMC1 and PGRMC2 with clinicopathological indicators and the clinical outcomes of the HCC patients. We knocked down or overexpressed PGRMC1 in HCC cell lines to evaluate its biological significance in HCC cell proliferation, differentiation, migration, and invasion.RESULTSWe found that few HCC cases expressed ER (5.6%) and PR (4.5%). In contrast, most HCC cases expressed PGRMC1 (89.9%) and PGRMC2 (100%). PGRMC1 and PGRMC2 exhibited significantly lower expression in tumor tissue than in non-tumor tissue (P < 0.001). Lower PGRMC1 expression in HCC was significantly associated with higher serum alpha-fetoprotein expression (P = 0.004), poorer tumor differentiation (P = 0.045) and liver capsule penetration (P = 0.038). Low PGRMC1 expression was an independent predictor for worse disease-free survival (P = 0.002, HR = 2.384, CI: 1.377-4.128) in our cases, as well as in the TCGA cohort (P < 0.001, HR = 2.857, CI: 1.781-4.584). The expression of PGRMC2 did not relate to patient outcome. PGRMC1 knockdown promoted a poorly differentiated phenotype and proliferation of HCC cells in vitro, while PGRMC1 overexpression caused the opposite effects.CONCLUSIONPGRMC1 is a non-classical hormonal receptor that negatively regulates hepatocarcinogenesis. PGRMC1 down-regulation is associated with progression of HCC and is a poor prognostic indicator.
Although mass spectrometry-based plasma proteomics enables sensitive and large-scale discovery and validation of biomarkers for various diseases, its integrative application to hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) is not well investigated. Therefore, we analyzed albumin-and immunoglobulin G-depleted plasma samples from 148 and 60 patients with HCC and CCA, respectively, using liquid chromatography-tandem mass spectrometry. The algorithm used to measure the content of each protein was the percentage of exponentially modified protein abundance index. From 5320 proteins assayed in plasma, 53 and 25 biomarker candidates were identified for HCC and CCA, respectively. The abundance of six and two HCC markers particularly protruded in stage II and III, respectively, whereas plasma serine protease inhibitor was the sole marker the level of which steadily decreased with CCA progression. From a prognostic facet, we showed candidate markers and their cutoff levels for evaluating probability of tumor recurrence and patient survival period. Combination Kaplan-Meier models showed that HCC stage III or IV and both the content of alpha-2-HS-glycoprotein and apolipoprotein CIII <0.2% exhibited the poorest post-surgical recurrence-free and overall survivals. Furthermore, the content of afamin �0.2% played a significant role on the poor prognosis in patients with CCA. Our findings, taken together, characterized novel plasma biomarker signatures in dissecting tumor stages and post-surgical outcomes of HCC and CCA.
The incidence of thyroid cancer is influenced by many factors including socioeconomic status. As economic conditions have improved in Taiwan, the increased frequency of medical examinations in the general population has led to earlier diagnosis of this indolent malignancy. The purpose of this retrospective study was to compare the clinical characteristics of cases of papillary thyroid cancer diagnosed over a 6-year period from 1993 to 1998 with those patients diagnosed from 1977 to 1992 at a single medical center. Of the 1,485 pathologically verified cases of thyroid cancer from 1977 to 1998, 1,093 had papillary thyroid carcinoma. The mean age of these patients was 40.4 ± 14.6 years. In order to identify trends in the characteristics of patients with thyroid cancer, patients were divided into those diagnosed before and those diagnosed after 1993. Patients diagnosed in these two time periods were also categorized into disease-free or non-disease-free groups depending on their status at the end of 1998. Actuarial survival rates were calculated using the Kaplan-Meier method. Multivariate analysis was performed to assess the independent effect of these variables using the Cox model. By December 1998, 61 (5.6%) of the 1,093 patients with papillary thyroid carcinoma had died. Among them, only 35 (3.2%) patients had died of thyroid cancer. The 5-year Greenwood survival probabilities for the groups diagnosed before and after 1993 were 0.9412 and 0.9817, respectively. The patients diagnosed after 1993 received more aggressive surgical procedures, had smaller tumor size, lower postoperative thyroglobulin levels, less advanced clinical stage at the time of diagnosis, showed more disease-free survival, and a lower mortality rate. In conclusion, the results of this study show that patients with a diagnosis of papillary thyroid cancer after 1993 had a smaller tumor size and a better prognosis than those diagnosed before 1993. This finding emphasizes the importance of early detection in thyroid cancer.
Hepatobiliary cancer is the third leading cause of cancer death worldwide. Appropriate markers for early diagnosis, monitoring of disease progression, and prediction of postsurgical outcome are still lacking. As the majority of circulating N ‐glycoproteins are originated from the hepatobiliary system, we sought to explore new markers by assessing the dynamics of N ‐glycoproteome in plasma samples from patients with hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), or combined HCC and CCA (cHCC‐CCA). Using a mass spectrometry‐based quantitative proteomic approach, we found that 57 of 5358 identified plasma proteins were differentially expressed in hepatobiliary cancers. The levels of four essential proteins, including complement C3 and apolipoprotein C‐III in HCC, galectin‐3‐binding protein in CCA, and 72 kDa inositol polyphosphate 5‐phosphatase in cHCC‐CCA, were highly correlated with tumor stage, tumor grade, recurrence‐free survival, and overall survival. Postproteomic site‐specific N ‐glycan analyses showed that human complement C3 bears high‐mannose and hybrid glycoforms rather than complex glycoforms at Asn85. The abundance of complement C3 with mannose‐5 or mannose‐6 glycoform at Asn85 was associated with HCC tumor grade. Furthermore, stepwise Cox regression analyses revealed that HCC patients with a hybrid glycoform at Asn85 of complement C3 had a lower postsurgery tumor recurrence rate or mortality rate than those with a low amount of complement C3 protein. In conclusion, our data show that particular plasma N ‐glycoproteins with specific N ‐glycan compositions could be potential noninvasive markers to evaluate oncological status and prognosis of hepatobiliary cancers.
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