MMP-20 Is Predominately a Tooth-Specific Enzyme with a Deep Catalytic Pocket that Hydrolyzes Type V Collagen †

Matrix metalloproteinase-20 (MMP-20, enamelysin) has a highly restricted pattern of expression. In healthy tissues, MMP-20 is observed in the enamel organ and pulp organ of developing teeth and is present only as an activated enzyme. To identify other tissues that may express MMP-20, we performed a systematic mouse tissue expression screen. Among the non-tooth tissues assayed, MMP-20 transcripts were only identified in minute quantities within the large intestine. The murine Mmp20 promoter was cloned, sequenced and assessed for potential tooth-specific regulatory elements. In silico analysis identified four promoter modules that were common to Mmp20 and at least two of three co-regulated predominantly tooth-specific genes that encode ameloblastin, amelogenin, and enamelin. We asked if the highly restricted MMP-20 expression pattern was associated with a broad substrate specificity that might preclude its expression in other tissues. An iterative mixture-based random doedecamer peptide library screen with Edman sequencing of MMP-20 cleavage products revealed that, among MMPs previously screened, MMP-20 had unique substrate preferences. These preferences indicate that MMP-20 has a deep and wide catalytic pocket that can accommodate substrates with large aromatic residues in the P1′ position. Based on matrices derived from the peptide library data, we identified and then confirmed that Type V collagen is an MMP-20 substrate. Since Type V collagen is not present in dental enamel but is an otherwise widely distributed collagen, and since only active MMP-20 has been observed in teeth, our data suggests that control of MMP-20 activity is primarily regulated by transcriptional means

SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas

Lineage survival oncogenes are activated by somatic DNA alterations in cancers arising from the cell lineages in which these genes play a role in normal development.1,2 Here we show that a peak of genomic amplification on chromosome 3q26.33, found in squamous cell carcinomas (SCCs) of the lung and esophagus, contains the transcription factor gene SOX2—which is mutated in hereditary human esophageal malformations3 and necessary for normal esophageal squamous development4, promotes differentiation and proliferation of basal tracheal cells5 and co-operates in induction of pluripotent stem cells.6,7,8 SOX2 expression is required for proliferation and anchorage-independent growth of lung and esophageal cell lines, as shown by RNA interference experiments. Furthermore, ectopic expression of SOX2 cooperated with FOXE1 or FGFR2 to transform immortalized tracheobronchial epithelial cells. SOX2-driven tumors show expression of markers of both squamous differentiation and pluripotency. These observations identify SOX2 as a novel lineage survival oncogene in lung and esophageal SCC

Patterns in Dysregulated, Non-mutated Cancer Mediator Gene Expression

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Biomedical Genetics, 2017.Genes dysregulated synergistically in response to oncogenic Ras and p53 mutations in young adult mouse colon (YAMC) cells are critical to the cancer phenotype at high frequency in transformed YAMC cells and a variety of human cancer cell lines. We found dysregulation of these genes, termed ‘cooperation response genes’ (CRGs), in 33 microarray gene expression datasets. Certain CRGs were frequently dysregulated with consistent directionality. Upon analysis of gene expression and somatic mutation data from The Cancer Genome Atlas and dbGAP, we discovered that despite widespread dysregulation, CRG expression was independent of the presence or absence of Ras or p53 mutations in cancer. However, a set of p53 response genes was highly differentially expressed in cancers with a p53 mutation. We investigated CRG dysregulation in precursor lesions in colon cancer and discovered that CRG dysregulation emerges at different points in the process of carcinogenesis. Our results suggest that CRG dysregulation is an essential and conserved element in the underlying regulatory architecture that brings about the malignant phenotype. Prostate cancer is the most common form of cancer among US men, with an increasing incidence due to the aging population. Patients diagnosed with clinically localized disease identified as intermediate or high-risk are typically treated by radical prostatectomy. Approximately 33% of these patients will suffer recurrence after surgery. Identifying patients likely to experience recurrence after radical prostatectomy would lead to improved clinical outcomes, as these patients could receive adjuvant radiotherapy. We developed a new tool for the prediction of prostate cancer recurrence based on the expression pattern of a small set of CRGs. We show that CRGs are systemically dysregulated in a new prostate cancer data set, including a 4-gene signature (HBEGF, HOXC13, IGFBP2, and SATB1) capable of differentiating recurrent from non-recurrent prostate cancer. To develop a suitable diagnostic tool to predict disease outcomes in individual patients, multiple algorithms and data handling strategies were evaluated on a training set using leave-one-out cross-validation (LOOCV). The best-performing algorithm, when used in combination with a predictive nomogram based on clinical staging, predicted recurrent and non-recurrent disease outcomes in a blinded validation set with 83% accuracy, outperforming previous methods. This test allows us to accurately identify prostate cancer patients likely to experience future recurrent disease, and demonstrates the potential for using CRG expression in predicting tumor phenotypic behavior

An Atypical Presentation of Hemophagocytic Lymphohistiocytosis (HLH) Secondary to Occult Hodgkin Lymphoma

Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening syndrome of immune system dysregulation characterized by the phagocytosis of various cells by histiocytes in the bone marrow. HLH can present in one of the two ways: primary HLH, which is caused by mutations in genes essential to T and NK-cell function, and secondary HLH, typically caused by Epstein–Barr virus (EBV) infection or malignancy. Because of the rapid progression and high mortality of this disease, prompt diagnosis is essential to good outcomes. Here, we report the 2-month clinical course of a patient who presented with altered mental status and recurrent fever of unknown origin. Initially, he did not meet diagnostic criteria for HLH and had a negative bone marrow biopsy; however, he eventually progressed to full-blown HLH secondary to occult Hodgkin lymphoma. This case is unusual for the slow and smoldering course of the patient’s disease and highlights the importance of aggressively searching for potential malignancies to ensure the initiation of definitive therapy as soon as possible

An Unusual Case of Multiple Myeloma with Light-Chain Cast Nephropathy Secondary to a Very Large Plasmacytoma without Bone Marrow Involvement

Here, we report a case of a patient who presented to Strong Memorial Hospital with new-onset renal failure and anemia and was found to have multiple myeloma with lambda light-chain cast nephropathy secondary to a very large (14 cm × 14 cm × 12 cm) plasmacytoma without bone marrow involvement. This case is notable as solitary plasmacytomas are almost never seen with concomitant myeloma-defining CRAB criteria or significantly elevated serum free light-chain ratios. Although solitary plasmacytomas are typically definitively treated with radiation, this case highlights that systemic treatment may be helpful in certain clinical scenarios

SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas

Lineage-survival oncogenes are activated by somatic DNA alterations in cancers arising from the cell lineages in which these genes play a role in normal development. Here we show that a peak of genomic amplification on chromosome 3q26.33 found in squamous cell carcinomas (SCCs) of the lung and esophagus contains the transcription factor gene SOX2, which is mutated in hereditary human esophageal malformations, is necessary for normal esophageal squamous development, promotes differentiation and proliferation of basal tracheal cells and cooperates in induction of pluripotent stem cells. SOX2 expression is required for proliferation and anchorage-independent growth of lung and esophageal cell lines, as shown by RNA interference experiments. Furthermore, ectopic expression of SOX2 here cooperated with FOXE1 or FGFR2 to transform immortalized tracheobronchial epithelial cells. SOX2-driven tumors show expression of markers of both squamous differentiation and pluripotency. These characteristics identify SOX2 as a lineage-survival oncogene in lung and esophageal SCC