Yee-Jee Jan

Phosphorylation of focal adhesion kinase at Tyr397 in gastric carcinomas and its clinical significance.

Focal adhesion kinase (FAK) has been implicated in tumorigenesis in various cancers; however, it remains unclear how FAK participates in tumor malignancy in vivo. This study seeks to understand the role of FAK activation in gastric cancer progression. Using immunohistochemical staining and Western blotting, we found that pY397 FAK, an autophosphorylation site on FAK activation, was abundant in the cancerous tissues of 21 of 59 patients with gastric carcinomas. We attempted to correlate clinicopathological parameters, including histological types, TNM staging, and cancer recurrence, with the expression of FAK and pY397 FAK in cancerous tissues. Intriguingly, patients with higher levels of pY397 FAK displayed higher incidences of gastric cancer recurrence after surgery and poor 5-year recurrence-free survival. Furthermore, multivariate analyses showed that pY397 FAK was an independent predictor of gastric cancer recurrence. As a result, expression of pY397 FAK is a significant prognostic factor for the recurrence of gastric cancer. Additionally, in vitro studies showed that overexpression of Y397F, a dominant-negative mutant of FAK, in AGS human gastric carcinoma cells impaired cell migration, invasion, and proliferation compared with cells overexpressing wild-type FAK. Thus, activation of FAK through autophosphorylation at Tyr397 leads to the progression of gastric carcinomas by promoting cell migration, invasion, and proliferation. Collectively, our results have provided valuable insights for the development of novel diagnoses and therapeutic targets for gastric cancer treatments.

14-3-3ε Overexpression Contributes to Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma

Background 14-3-3ε is implicated in regulating tumor progression, including hepatocellular carcinoma (HCC). Our earlier study indicated that elevated 14-3-3ε expression is significantly associated with higher risk of metastasis and lower survival rates of HCC patients. However, the molecular mechanisms of how 14-3-3ε regulates HCC tumor metastasis are still unclear. Methodology and Principal Findings In this study, we show that increased 14-3-3ε expression induces HCC cell migration and promotes epithelial-mesenchymal transition (EMT), which is determined by the reduction of E-cadherin expression and induction of N-cadherin and vimentin expression. Knockdown with specific siRNA abolished 14-3-3ε-induced cell migration and EMT. Furthermore, 14-3-3ε selectively induced Zeb-1 and Snail expression, and 14-3-3ε-induced cell migration was abrogated by Zeb-1 or Snail siRNA. In addition, the effect of 14-3-3ε-reduced E-cadherin was specifically restored by Zeb-1 siRNA. Positive 14-3-3ε expression was significantly correlated with negative E-cadherin expression, as determined by immunohistochemistry analysis in HCC tumors. Analysis of 14-3-3ε/E-cadherin expression associated with clinicopathological characteristics revealed that the combination of positive 14-3-3ε and negative E-cadherin expression is significantly correlated with higher incidence of HCC metastasis and poor 5-year overall survival. In contrast, patients with positive 14-3-3ε and positive E-cadherin expression had better prognostic outcomes than did those with negative E-cadherin expression. Significance Our findings show for the first time that E-cadherin is one of the downstream targets of 14-3-3ε in modulating HCC tumor progression. Thus, 14-3-3ε may act as an important regulator in modulating tumor metastasis by promoting EMT as well as cell migration, and it may serve as a novel prognostic biomarker or therapeutic target for HCC.

Overexpression of 14-3-3ε predicts tumour metastasis and poor survival in hepatocellular carcinoma.

Ko B‐S, Chang T‐C, Hsu C, Chen Y‐C, Shen T‐L, Chen S‐C, Wang J, Wu K K, Jan Y‐J & Liou J‐Y
(2011) Histopathology58, 705–711
Overexpression of 14‐3‐3ε predicts tumour metastasis and poor survival in hepatocellular carcinoma

Synchronous Gastric Gastrointestinal Stromal Tumor and Signet-Ring Cell Adenocarcinoma: A Case Report:

Synchronous tumors of the stomach are uncommon. We present a unique case of gastric synchronous tumors composed of signet-ring cell adenocarcinoma and gastrointestinal stromal tumor (GIST). The two tumors arose at the same site and were sharply juxtaposed without intermingling of morphologically distinct elements. Coincidence probably accounts for this occurrence, even if a common carcinogenic agent had been hypothesized. Preoperative imaging and endoscopic biopsy could lead to the suspicion of synchronous tumors, and an accurate histological identification of both tumors could be achieved by multiple deep endoscopic biopsies. The presence in our case of diffuse carcinomatosis indicates that the signet-ring cell adenocarcinoma had a greater adverse effect on the prognosis than the GIST.

Combined Primary Neuroendocrine Carcinoma and Hepatocellular Carcinoma of the Liver

We report a unique case of combined primary neuroendocrine carcinoma (NEC) and hepatocellular carcinoma (HCC) of the liver in a 65-year-old male patient. The patient underwent segmental resection of the liver and regional lymph node dissection for a tumor mass that measured 7.5 cm in diameter in the right lobe, with regional lymphadenopathy. Histologically, the hepatic tumor was composed of predominantly small-cell NEC, but admixed with a small island of moderately differentiated HCC. We speculate that the NEC originated from a poorly differentiated tumor clone of an HCC that underwent neuroendocrine differentiation, and that this tumor was now at the end stage of the transitional period from HCC to NEC, based on the small amount of disappearing HCC. Ki-67 and p53 expression were higher in the NEC than in the HCC, and the lymph nodes showed only metastatic NEC. Therefore, this kind of tumor had a more aggressive clinical course in accordance with being an NEC rather than a conventional HCC. Three months after operation, the patient had multiple recurrent tumor nodules within the liver, spreading the metastasis to the adrenal glands and para-aortic lymph nodes. The patient died 1 year after operation.

Overexpressed focal adhesion kinase predicts a higher incidence of extrahepatic metastasis and worse survival in hepatocellular carcinoma

Focal adhesion kinase plays a critical role in cancer progression, invasion, and metastasis. Although focal adhesion kinase overexpression indicates poor prognoses for hepatocellular carcinoma, its role in hepatocellular carcinoma metastasis has not been well investigated. In this study, 55 hepatocellular carcinoma patients were enrolled, and their primary liver tumors as well as 18 matched metastases were subjected to semiquantitative immunohistochemistry analysis of focal adhesion kinase expression. Overexpression of focal adhesion kinase was observed in 34 (61.8%) of 55 primary tumors and significantly predicted subsequent extrahepatic metastases (P = .04). Metastatic tumors expressed higher focal adhesion kinase than their matched primaries (P = .010). Focal adhesion kinase overexpression indicated both worse overall 5-year survival rate (51.5% +/- 8.7% versus 90.2% +/- 6.6%; P = .004) and 5-year progression-free survival rate (51.5% +/- 8.7% versus 90.2% +/- 6.6%; P = .041). Taken together, we demonstrated here that focal adhesion kinase expression is significantly related to subsequent hepatocellular carcinoma metastasis. Focal adhesion kinase is thus considered as a reasonable target for novel therapies against hepatocellular carcinoma progression and metastasis.

Spinal atypical teratoid/rhabdoid tumor in a 7‐year‐old boy

Reported herein is an unusual case of atypical teratoid/rhabdoid tumor (AT/RT) of the lumbar spine with an intradural extramedullary location in a 7‐year‐old boy. Histologically, this tumor contained rhabdoid cells, pale cells, and sickle‐shaped embracing cells without primitive neuroectodermal tumor (PNET), mesenchymal or epithelial components. Immunohistochemical staining showed that these tumor cells react positively for epithelial membrane antigen (EMA), vimentin, cytokeratin (AE1/AE3), CD99 and neurofilament protein, but negatively for INI1 antibody. Chromosome 22q deletion was demonstrated on fluorescence in situ hybridization.

Involvement of 14-3-3 Proteins in Regulating Tumor Progression of Hepatocellular Carcinoma

There are seven mammalian isoforms of the 14-3-3 protein, which regulate multiple cellular functions via interactions with phosphorylated partners. Increased expression of 14-3-3 proteins contributes to tumor progression of various malignancies. Several isoforms of 14-3-3 are overexpressed and associate with higher metastatic risks and poorer survival rates of hepatocellular carcinoma (HCC). 14-3-3β and 14-3-3ζ regulate HCC cell proliferation, tumor growth and chemosensitivity via modulating mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK) and p38 signal pathways. Moreover, 14-3-3ε suppresses E-cadherin and induces focal adhesion kinase (FAK) expression, thereby enhancing epithelial-mesenchymal transition (EMT) and HCC cell migration. 14-3-3ζ forms complexes with αB-crystallin, which induces EMT and is the cause of sorafenib resistance in HCC. Finally, a recent study has indicated that 14-3-3σ induces heat shock protein 70 (HSP70) expression, which increases HCC cell migration. These results suggest that selective 14-3-3 isoforms contribute to cell proliferation, EMT and cell migration of HCC by regulating distinct targets and signal pathways. Targeting 14-3-3 proteins together with specific downstream effectors therefore has potential to be therapeutic and prognostic factors of HCC. In this article, we will overview 14-3-3’s regulation of its downstream factors and contributions to HCC EMT, cell migration and proliferation.

Expression of partitioning defective 3 (Par-3) for predicting extrahepatic metastasis and survival with hepatocellular carcinoma.

Partitioning defective 3 (Par-3), a crucial component of partitioning-defective complex proteins, controls cell polarity and contributes to cell migration and cancer cell epithelial-to-mesenchymal transition. However, the clinical relevance of Par-3 in tumor progression and metastasis has not been well elucidated. In this study, we investigated the impact and association of Par-3 expression and clinical outcomes with hepatocellular carcinoma (HCC). We first confirmed that Par-3 was abundantly expressed in HCC cell lines by Western blot analysis. We used immunohistochemistry to analyze the association of Par-3 expression and clinicopathological characteristics in primary and subsequent metastatic tumors of patients with HCC. Par-3 was overexpressed in 47 of 111 (42.3%) primary tumors. Increased expression of Par-3 in primary tumors predicted an increased five-year cumulative incidence of extrahepatic metastasis. In addition, multivariate analysis revealed that Par-3 overexpression was an independent risk factor of extrahepatic metastasis. Increased Par-3 expression in primary tumors was associated with poor five-year overall survival rates and was an independent prognostic factor on Cox regression analysis. In conclusion, we show for the first time that increased Par-3 expression is associated with distant metastasis and poor survival rates in patients with HCC. Par-3 may be a novel prognostic biomarker and therapeutic target for HCC.

Involvement of 14-3-3γ overexpression in extrahepatic metastasis of hepatocellular carcinoma.

The 14-3-3γ protein is an important regulator of various cellular and physiologic functions. Overexpression promotes cell proliferation and induces cancer cell polyploidization. Production is up-regulated in human hepatocellular carcinoma. However, the clinical significance of 14-3-3γ for human hepatocellular carcinoma metastasis and survival has not been clarified. In this study, 55 patients with human hepatocellular carcinoma were enrolled; and 18 of them were identified as having extrahepatic metastases. Expression of 14-3-3γ in these primary and metastatic samples was measured with semiquantitative immunohistochemistry analysis. Overexpression of 14-3-3γ was observed in 38 (69.1%) of the primary tumors, correlated significantly with a high α-fetoprotein concentration (P = .003), and predicted a higher probability of extrahepatic metastasis (cumulative probabilities at 5 years: 42.2% ± 8.0% versus 5.9% ± 5.7%, 14-3-3γ positive versus negative; P = .012). Furthermore, 14-3-3γ overexpression was associated with a worse 5-year overall survival rate (81.6% ± 9.6% versus 59.5% ± 8.1%, respectively) and a worse 5-year progression-free survival rate (75.6% ± 10.6% versus 48.6% ± 8.2%, respectively). Elevated expression of 14-3-3γ in human hepatocellular carcinoma predicts extrahepatic metastasis and worse survival. The protein thus is a candidate biomarker and a potential target for novel therapies against human hepatocellular carcinoma progression and metastasis.