Nuclear EpICD expression and its role in hepatocellular carcinoma.

Regulated intramembrane proteolysis of epithelial cell adhesion molecule (EpCAM) results in shedding of the extracellular domain (EpEX) and release of the intra-cellular domain (EpICD) into the cytoplasm. Released EpICD associates with FHL2, ß-catenin and Lef-1 to form a nuclear complex and triggers oncogenic signaling. This study was conducted to examine the nuclear expression of EpICD in hepatocellular carcinoma (HCC) and to assess the role of EpICD in HCC. EpICD immunoexpression was examined in 100 cases of HCC using tissue microarrays and correlated with clinicopathological parameters. We also examined the role of EpICD in HCC using EpICD cDNA transfected HCC cell line and EpCAM silenced HCC cell line by small interfering RNA (siRNA). Nuclear expression of EpICD was observed in 19 of 100 (19%) cases. Nuclear expression of EpICD significantly correlated with nuclear expression of ß-catenin, and Ki-67 labeling index. In addition, nuclear expression of EpICD was associated with higher histologic grade and advanced T category. Forced overexpression of EpICD in the HCC cell significantly increased the cell proliferation, migration and invasion. The overexpression of EpICD also increased the expression levels of the active form of ß-catenin and c-myc and cyclin D1. In contrast, downregulation of EpCAM by siRNA decreased the cell proliferation, migration, invasion and the expression of active form of ß-catenin, c-myc and cyclin D1. Our present data suggest that EpICD plays important roles in HCC progression by modulating expression of target genes of EpCAM.

C-KIT-positive undifferentiated tumor of the liver: A case report.

With recent advances in cancer stem cell analysis, it has been postulated that the transformation of hepatic stem and progenitor cells underlies the development of certain liver cancers. Human C-KIT is a transmembrane type III receptor protein with intrinsic tyrosine kinase activity that has been proposed as a marker for human embryonic stem cells. In addition, human C-KIT functions in maintaining the undifferentiated state of stem cells, and has been identified as a marker for human hematopoietic and hepatic stem/progenitor cells. The present study identified an unusual case of a C-KIT-positive hepatic tumor with an undifferentiated stem cell phenotype distinct from existing descriptions of liver tumors. A 69-year-old male with Ampulla of Vater (AoV) cancer was admitted to the hospital for the treatment of a hepatic mass that was incidentally detected during evaluation of AoV cancer. Microscopically, the hepatic tumor was composed of solidly packed small, round and uniform undifferentiated cells, which resembled that of a small-blue-round-cell tumor. The immunophenotype of neoplastic cells (C-KIT+/EpCAM+/E-cadherin+/keratin 7-/keratin 19-/α-fetoprotein-/albumin-) supported primitive stem cell features with no hepatic or biliary phenotypes. Polymerase chain reaction and direct DNA sequencing revealed no C-KIT mutations. It is suggested that this tumor may have originated from transformed C-KIT+/EpCAM+/E-cadherin+ cells, which are more primitive and undifferentiated than bipotential hepatic progenitor cells.

Abdominal fibromatosis in a young child: a case study and review of the literature.

Fibromatoses comprise many different entities of well-differentiated fibroblastic proliferation with variable collagen production and form a firm nodular mass. Abdominal fibromatosis is distinguishable from other forms of fibromatosis because of its location and its tendency to occur in women of childbearing age during or following pregnancy. Abdominal fibromatosis in children is an extremely rare condition. A 15-month-old boy presented with an abdominal wall mass that had recently increased in size. Mass excision was perfomed. The tumor was 4.3×4.1 cm and partly circumscribed. Histologically, the tumor was composed of parallel long fascicles of spindle-cells with a uniform appearance. The edges of the resected mass were infiltrative, and the surgical margins were positive. Mitotic figures were <1/10 high power fields. No cellular atypia or necrosis was present. The tumor cells were positive for vimentin and nuclear ß-catenin staining.

Expression of CHOP in squamous tumor of the uterine cervix.

BACKGROUND: High-risk human papillomavirus (HR-HPV) infection and abnormal p53 expression are closely involved in carcinogenesis of squamous cell carcinoma (SqCC) of uterine cervix. Recent studies have suggested that virus-induced endoplasmic reticulum (ER) stress modulates various cell survival and cell death signaling pathways. The C/EBP homologous protein (CHOP) is associated with ER stress-mediated apoptosis and is also involved in carcinogenesis of several human cancers. We hypothesized that CHOP is involved in the carcinogenesis of uterine cervical cancer in association with HR-HPV and/or p53. METHODS: Immunohistochemistry was used to analyze CHOP and p53 protein expression of tissue sections from 191 patients with invasive cancer or preinvasive lesions of the uterine cervix (61 cases of SqCC, 66 cases of cervical intraepithelial neoplasia [CIN] III, and 64 cases of CIN I). RESULTS: CHOP was expressed in 59.4% of CIN I, 48.5% of CIN III, and 70.5% of SqCC cases. It was also significantly more frequent in invasive SqCC than in preinvasive lesions (p=0.042). Moreover, CHOP expression significantly correlated with HR-HPV infection and p53 expression (p=0.009 and p=0.038, respectively). CONCLUSIONS: Our results suggest that CHOP is involved in the carcinogenesis of the uterine cervix SqCC via association with HR-HPV and p53.

Papillary carcinoma of thyroid metastatic to adenocarcinoma in situ of lung: report of an unusual case.

The tumor-to-tumor metastasis is a rare event. The lung tumors are the most common donor tumors in tumor-to-tumor metastasis, but are exceedingly rare as a recipient. Here, we report a case of papillary thyroid carcinoma (PTC) metastasizing to adenocarcinoma in situ (AIS, formerly bronchioloalveolar carcinoma) of the lung in a 44-year-old woman who underwent total thyroidectomy for PTC 8 years ago. To the best of our knowledge, the present case is the first case reporting on PTC metastasized to AIS. A review of the relevant literature is presented.

Expression of keratin 20 and its clinicopathological significance in intrahepatic cholangiocarcinoma.

Although the expression of keratin 7 (K7) and K20 is considered to be a useful factor in the differential diagnosis of intrahepatic cholangiocarcinoma (ICC) and metastatic colorectal carcinoma (CRC) of the liver, a proportion of typical ICC retains K20 expression. The frequency and biological significance of K20 expression in ICC remains unclear. We analyzed the expression of K7, K19 and K20 in 66 surgically resected liver tumors consisting of 46 ICCs and 20 metastatic CRCs of the liver and 20 corresponding primary CRCs. In the 46 ICCs, K7, K19 and K20 were expressed in 40 (87%), 45 (98%) and 16 (35%) cases, respectively. K7, K19 and K20 were expressed in 1 (5%), 20 (100%) and 16 (80%) of the 20 primary CRCs and 2 (10%), 20 (100%) and 16 (80%) of the 20 metastatic CRCs, respectively. A combined K7/K20 profile was identified as a good predictor for differentiating ICC and metastatic CRC. K20 expression in ICC was significantly associated with male gender (P=0.034), hilar location (P=0.026), intraductal papillary type (P=0.006), intestinal phenotype (P<0.001) and MUC2 expression (P=0.008). Univariate analysis identified that poor patient survival was significantly associated with histological grade (P=0.020), invasion depth (P=0.005), lymph node metastasis (P=0.012), tumor stage (P=0.004) and vessel invasion (P=0.023). The tumor stage (P=0.002) was a poor independent prognostic indicator, while MUC6 expression (P=0.036) was a good independent prognostic indicator. The survival rate in patients with K20-positive ICC was lower compared to that of patients with K20-negative ICC, but was not statistically significant. Furthermore, the combined K7/K20 immunophenotype was identified to be useful for differentiating ICC and metastatic CRC. K20-positive ICC displays specific characteristics with regards to tumor location and histological subtype. Additionally, MUC6 expression in ICC is a good independent prognostic factor, while K20 expression is more often associated with aggressive biological behavior.

Expression of ER stress and autophagy-related molecules in human non-small cell lung cancer and premalignant lesions.

Stress that impairs endoplasmic reticulum (ER) function leads to an accumulation of unfolded or misfolded proteins in the ER (ER stress). Autophagy is a lysosomal pathway involved in the turnover of cellular macromolecules and organelles, which emerging data indicate that ER stress is also a potent inducer of autophagy. ER stress and autophagy are involved in human cancer. We examined the expression of ER stress-related proteins [GRP78 and C/EBP homologous protein (CHOP)] and autophagic proteins (Beclin-1 and LC3) in non-small cell lung carcinomas (NSCLCs), bronchioloalveolar carcinomas (BACs) and atypical adenomatous hyperplasias (AAHs) to understand their role in the NSCLC pathogenesis. The expression of GRP78 and CHOP, Beclin-1 and LC3 were analyzed using immunohistochemistry on tissue sections from 133 NSCLC (69 squamous cell carcinomas, 56 adenocarcinomas (AC) and eight other NSCLCs), 21 BAC and 9 AAH. Expression of GRP78 and Beclin-1 was correlated with low tumor stage (p < 0.001 and p = 0.019, respectively) and longer survival (p = 0.007 and p <0.001, respectively) by Kaplan-Meier analysis. However, CHOP was correlated with high tumor stage (p = 0.038) and shorter survival (p = 0.012). Expression of GRP78 and Beclin-1 was positively correlated (p = 0.006). Our study showed that the expression of GRP78, CHOP, Beclin-1 and LC3 in lung cancer and its relation with clinicopathologic factors and patients survival. These results suggest that GRP78, CHOP and Beclin-1 may play an important role in tumorigenesis of lung AC and may serve as new prognostic indicators for outcome of the patients with NSCLC.