KOC (K homology domain containing protein overexpressed in cancer): a novel molecular marker that distinguishes between benign and malignant lesions of the pancreas

ArticleinAmerican Journal of Surgical Pathology 29(2):188-95 · February 2005with20 Reads
Impact Factor: 5.15 · Source: PubMed
Abstract

KOC (K homology domain containing protein overexpressed in cancer) is a novel oncofetal RNA-binding protein highly expressed in pancreatic carcinomas. Recently, Corixa Corporation developed a monoclonal antibody specific for KOC that can be used with standard immunohistochemical techniques. The purposes of this study were 1) to assess KOC mRNA expression in pancreatic carcinoma, 2) to determine the pattern of KOC immunoexpression among benign, borderline, and malignant pancreatic epithelial lesions, and 3) to evaluate the utility of the KOC antibody in distinguishing between these entities. mRNA was isolated from fresh pancreatic tissues (19 carcinomas, 2 normal pancreas, 1 chronic pancreatitis) and amplified using standard RT-PCR techniques. Fifteen of 19 (79%) carcinomas overexpressed KOC mRNA relative to non-neoplastic tissue samples and expression increased progressively with tumor stage: the mean copy number of KOC mRNA transcripts was 1.5, 11.1, 31, and 28 for stage I, II, III, and IV carcinomas, respectively, compared with 0.9 and 1 for normal pancreatic tissue and chronic pancreatitis, respectively. Immunostains using the KOC antibody were performed on 50 surgical resection specimens (38 invasive adenocarcinomas, 3 intraductal papillary-mucinous neoplasms, 2 mucinous cystic neoplasms, 7 chronic pancreatitis). KOC staining was present in 37 of 38 (97%) carcinomas: the staining reaction was moderate or strong in 36 of 38 (94%) and present in >50% of the tumor cells in 35 of 38 (92%) cases. Severe dysplasia of the ductal epithelium, present in 19 foci of intraductal papillary mucinous carcinoma, mucinous cystadenocarcinoma, and grade 3 pancreatic intraepithelial neoplasia (PanIN3) showed strong or moderate staining in 15 (79%) cases, whereas foci of mild and moderate dysplasia (intraductal papillary-mucinous neoplasms and mucinous cystic neoplasms with adenoma and/or moderate dysplasia, PanIN1, and PanIN2) were uniformly negative for this marker in 25 and 22 cases, respectively. In the normal pancreas, weak background staining of acini was present in 12 of 50 (24%) cases but was easily distinguishable from the type of staining identified in neoplastic epithelium, and benign ducts and ductules were negative in all cases. Four of 38 (11%) foci of chronic pancreatitis, present in the 7 resections performed for chronic pancreatitis as well as 31 foci of peritumoral chronic pancreatitis, showed weak staining in <10% of the ductules. We conclude that KOC is a sensitive and specific marker for carcinomas and high-grade dysplastic lesions of the pancreatic ductal epithelium. Therefore, immunostains directed against KOC may be of diagnostic utility in the evaluation of pancreatic lesions, particularly when biopsy material is limited.

    • "... differentiated PDAC. Expression of Igf2bps increase progressively with PDAC tumor stage (Yantiss et al., 2005) and high levels of Igf2bps in PDAC correlate with increased metastasis and extremely poor survival..."
      Consistently, upregulated genes downstream of Lin28b, includes the oncofetal RNA-binding proteins Igf2bp1 and 3 that have been associated with poorly differentiated PDAC. Expression of Igf2bps increase progressively with PDAC tumor stage (Yantiss et al., 2005) and high levels of Igf2bps in PDAC correlate with increased metastasis and extremely poor survival outcome (Schaeffer et al., 2010; Taniuchi et al., 2014). In this context, we observed signs of both accelerated initiation (increased number of PanIN) as well as increased metastatic potential in mice expressing high levels of Lin28b and Igf2bps.
    [Show abstract] [Hide abstract] ABSTRACT: Chromatin remodeling proteins are frequently dysregulated in human cancer, yet little is known about how they control tumorigenesis. Here, we uncover an epigenetic program mediated by the NAD+-dependent histone deacetylase Sirtuin 6 (SIRT6) that is critical for suppression of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies. SIRT6 inactivation accelerates PDAC progression and metastasis via upregulation of Lin28b, a negative regulator of the let-7 microRNA. SIRT6 loss results in histone hyperacetylation at the Lin28b promoter, Myc recruitment, and pronounced induction of Lin28b and downstream let-7 target genes, HMGA2, IGF2BP1, and IGF2BP3. This epigenetic program defines a distinct subset with a poor prognosis, representing 30%–40% of human PDAC, characterized by reduced SIRT6 expression and an exquisite dependence on Lin28b for tumor growth. Thus, we identify SIRT6 as an important PDAC tumor suppressor and uncover the Lin28b pathway as a potential therapeutic target in a molecularly defined PDAC subset.
    No preview · Article · May 2016 · Cell
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    • "...of normal esophagus [20] , duode- num [41], ampullary [41], bile duct [29, 41], or pancreatic duct [41] epithelium, while weak immunoreactivity was identified in limited cases of normal colon epithelium ..."
      This antibody was generated following immunization of mice with purified recombinant IMP3 protein encoding amino acids 2–580 [41]. No immunoreactivity with this anti-IMP3 antibody was reported in samples of normal esophagus [20] , duode- num [41], ampullary [41], bile duct [29, 41], or pancreatic duct [41] epithelium, while weak immunoreactivity was identified in limited cases of normal colon epithelium [15]. Following incubation with HRP-conjugated secondary antibody, signals were detected using ECL-PLUS (GE Healthcare, Amersham, UK).
    [Show abstract] [Hide abstract] ABSTRACT: The biological characteristics and roles of insulin-like growth factor II mRNA-binding protein 3 protein (IMP3) expression in small-intestinal adenocarcinoma were investigated. The value of IMP3 immunostaining in the diagnosis of small-intestinal epithelial lesions was also evaluated. Immunohistochemical expression of IMP3 in normal small-intestinal mucosa adjacent to adenoma and adenocarcinoma lesions, and inflamed duodenal and ileal mucosa was analyzed. Samples assessed were: duodenal ulcer (n=6), Crohn’s disease (n=5), low-grade small-intestinal adenoma (n=10), high-grade small-intestinal adenoma (n=13), small-intestinal adenocarcinoma (n=23), lymph node metastases (LNM; n=7), and preoperative biopsies of small-intestinal adenocarcinoma (n=6). Immunohistochemical expression of Ki-67 and p53 was also analyzed in adenoma and adenocarcinoma samples. IMP3 was not expressed in normal epithelium, but weakly expressed in reparative epithelium. Meanwhile, increased IMP3 expression was associated with a higher degree of dysplasia in adenomas, higher T classification, LNM, Ki-67 positivity, histological differentiation, and lower 5-year disease-free survival, but not p53 expression in adenocarcinoma. IMP3 expression appears to be a late event in the small-intestinal carcinogenesis. Assessing the IMP3 staining pattern can be useful in the diagnosis of small-intestinal epithelial lesions when used in conjunction with other histological criteria.
    Preview · Article · Dec 2015 · Acta histochemica et cytochemica official journal of the Japan Society of Histochemistry and Cytochemistry
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    • "...icular IGF2BP1 and IGF2BP3, are potent biomarkers of aggressive and invasive pancreatic carcinomas [83]. ..."
      In agreement with other analyses, IGF2BP expression was determined in the vast majority of pancreatic ductal adenocarcinomas (PDAC) and was proposed for 97% of invasive PDACs [83]. In contrast, the vast majority (>74%) of inflamed pancreatic tissue was negative supporting the view that IGF2BPs, in particular IGF2BP1 and IGF2BP3, are potent biomarkers of aggressive and invasive pancreatic carcinomas [83].
    [Show abstract] [Hide abstract] ABSTRACT: The post-transcriptional control of gene expression mediated by RNA-binding proteins (RBPs), long non-coding RNAs (lncRNAs) as well as miRNAs is essential to determine tumor cell fate and thus is a major determinant in cancerogenesis. The IGF2 mRNA binding protein family (IGF2BPs) comprises three RBPs. Two members of the family, IGF2BP1 and IGF2BP3, are bona fide oncofetal proteins, which are de novo synthesized in various human cancers. In vitro studies revealed that IGF2BPs serve as post-transcriptional fine-tuners modulating the expression of genes implicated in the control of tumor cell proliferation, survival, chemo-resistance and metastasis. Consistently, the expression of both IGF2BP family members was reported to correlate with an overall poor prognosis and metastasis in various human cancers. Due to the fact that most reports used a pan-IGF2BP antibody for studying IGF2BP expression in cancer, paralogue-specific functions can barely be evaluated at present. Nonetheless, the accordance of IGF2BPs’ role in promoting an aggressive phenotype of tumor-derived cells in vitro and their upregulated expression in aggressive malignancies provides strong evidence that IGF2BPs are powerful post-transcriptional oncogenes enhancing tumor growth, drug-resistance and metastasis. This suggests IGF2BPs as powerful biomarkers and candidate targets for cancer therapy.
    Full-text · Article · Dec 2014 · Seminars in Cancer Biology
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