Key Points• PTPRK binds to STAT3 and directly dephosphorylates phospho-STAT3 at Tyr705.• Loss of PTPRK, located in the deleted 6q region, leads to STAT3 activation and contributes to nasal-type NK/ T-cell lymphoma pathogenesis. . Restoration of PTPRK inhibited tumor cell growth and reduced the migration and invasion ability of NKTCL cells. Monoallelic deletion and promoter hypermethylation caused underexpression of PTPRK messenger RNA in NKTCL, and methylation of the PTPRK promoter significantly correlated with inferior overall survival (P 5 .049) in NKTCL patients treated with the steroid-dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide regimen. Altogether, our findings show that PTPRK underexpression leads to STAT3 activation and contributes to NKTCL pathogenesis. (Blood. 2015;125(10):1589-1600

Esophageal squamous cell carcinoma (ESCC), the major histologic subtype of esophageal cancer, is a devastating disease characterized by distinctly high incidences and mortality rates. However, there remains limited understanding of molecular events leading to development and progression of the disease, which are of paramount importance to defining biomarkers for diagnosis, prognosis, and personalized treatment. By high-throughout transcriptome sequence profiling of nontumor and ESCC clinical samples, we identified a subset of significantly differentially expressed genes involved in integrin signaling. The Rab25 gene implicated in endocytic recycling of integrins was the only gene in this group significantly downregulated, and its downregulation was confirmed as a frequent event in a second larger cohort of ESCC tumor specimens by quantitative real-time PCR and immunohistochemical analyses. Reduced expression of Rab25 correlated with decreased overall survival and was also documented in ESCC cell lines compared with pooled normal tissues. Demethylation treatment and bisulfite genomic sequencing analyses revealed that downregulation of Rab25 expression in both ESCC cell lines and clinical samples was associated with promoter hypermethylation. Functional studies using lentiviral-based overexpression and suppression systems lent direct support of Rab25 to function as an important tumor suppressor with both anti-invasive and -angiogenic abilities, through a deregulated FAK-Raf-MEK1/2-ERK signaling pathway. Further characterization of Rab25 may provide a prognostic biomarker for ESCC outcome prediction and a novel therapeutic target in ESCC treatment. Cancer Res; 72(22); 6024-35. Ó2012 AACR.

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A retrospective single-center cohort study was conducted on 35 patients with diffuse proliferative (WHO type IV) and/or membranous (type V) lupus nephritis (22 with type IV, 6 with type V, and 7 with type IV plus V) who had been treated with a sequential regimen comprising prednisolone and cyclophosphamide during active disease, followed by low-dose prednisolone and azathioprine maintenance. The follow-up period was 33.2 ± 4.5 months. At presentation, 32 (91.4%) patients were nephrotic, and an abnormal serum cre-atinine level was noted in 14 (48.3%) patients with type IV changes. Cyclophosphamide was given for 26.8 ± 2.8 weeks. 33 (94.3%) patients achieved complete or partial renal remissions: 77.3 and 22.7% of the type IV patients, 16.7 and 66.6% of the type V patients, and 14.3 and 71.4% of the type IV plus V patients, respectively (p < 0.0001 for type IV versus type V and for type IV versus type IV plus V). The duration of therapy before renal remissions and normalization of C3 were attained was similar among the three groups of patients. Disease relapse occurred in 4 (18.2%) of 22 type IV patients and in 1 of the 5 type V patients in remission. Mortality was not observed, and none of the patients had an increase in serum creatinine level to double the baseline value. Adverse effects related to therapy included: hair loss (42.9%), transient amenorrhea (53.6%), leukopenia (11.4%), febrile episodes (14.3%), and herpes zoster (28.6%). We conclude that sequential use of prednisolone and cyclophosphamide followed by low-dose prednisolone and azathioprine can achieve favorable therapeutic results in the majority of patients with diffuse proliferative and/or membranous lupus nephritis, without excessive toxici-ties.

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The conserved oligomeric Golgi (COG) complex is an eight subunit protein involved in the retrograde transport of Golgi components. It affects the localization of several Golgi glycosyltransferases and hence is involved in N- and O-glycosylation. Genetic defects in this complex belong to the rapidly expanding family of congenital disorders of glycosylation (CDG). Patients have been reported with defects of subunit 1 (CDG1-CDG), subunit 4 (CDG4-CDG), subunit 5 (CDG5-CDG), subunit 6 (CDG6-CDG), subunit 7 (CDG7-CDG), and subunit 8 (CDG8-CDG). This paper is on the second reported patient with COG5-CDG. She showed a mild neurohepatic disease with central as well as peripheral neurological involvement while in the first reported patient (with a different mutation) only mild central neurological involvement was reported.

Whether particular Epstein‐Barr virus (EBV) strains are preferentially selected in malignant diseases remains controversial. Assessment of the importance of strain variation in the pathogenicity of EBV has been hampered principally by the lack of accurate data on the prevalence of virus variants in the normal population. To clarify this issue, a detailed comparative analysis of the EBV genomes contained in normal nasal and nasopharyngeal mucosal tissues and in nasal T/NK‐cell lymphoma, which originates at these anatomic sites, was carried out by PCR amplification across the 30‐bp deletion and the 33‐bp repeat loci in the LMP1 gene and the type‐specific polymorphic loci in the EBNA2 and EBNA3C genes and by sequence analysis of the 3' C‐terminal region of the LMP1 gene. Whilst the majority of EBV strains in either normal or tumour tissues were type 1 viruses with similar numbers of LMP1 repeats, a marked predominance of LMP1 deletion (del‐LMP1) over non‐deleted/wild‐type LMP1 (wt‐LMP1) variants was observed in nasal T/NK‐cell lymphoma. Although del‐LMP1 variants were also prevalent in the normal carriers of our population, wt‐LMP1 was detected at a significantly higher frequency in normal vs. tumour tissues (p = 0.036). More critically, wt‐LMP1 variants were found frequently in mixed infection with del‐LMP1 variants in the normal carriers. Sequence analysis identified 2 major del‐LMP1 (and several wt‐LMP1) variants containing signatory nucleotide changes in relation to the prototype B95–8 sequence in both normal and neoplastic nasal tissues. Together, our data provide strong evidence for a selection mechanism for del‐LMP1 over the wt‐LMP1 variants in tumours. Int. J. Cancer 80:356–364, 1999. © 1999 Wiley‐Liss, Inc.

LIM domain only 2 (LMO2) proteins are important regulators in determining cell fate and controlling cell growth and differentiation. This study has investigated LMO2 expression in human prostatic tissue specimens, prostate cancer cell lines, and xenografts; and has assessed the possible role and mechanism of LMO2 in prostate carcinogenesis. Immunohistochemical analysis on a tissue microarray consisting of 91 human prostate specimens, including normal, prostatic hyperplasia, high-grade prostatic intraepithelial neoplasia, and invasive carcinoma, revealed that overexpression of LMO2 was significantly associated with advanced tumour stage, as measured by Gleason score (p = 0.012), as well as with the development of distant metastasis (p = 0.018). These data were supported by quantitative real-time PCR experiments, where LMO2 mRNA levels were found to be significantly higher in prostate tumour specimen than in normal epithelium (p = 0.037). The expression of LMO2 in cell lines and xenografts representing androgen-dependent (AD) and androgen-independent (AI) prostate cancer stages was further studied. Consistent with the in vivo data, LMO2 mRNA and protein were found to be overexpressed in the more aggressive AI cells (PC3, DU145, and AI CWR22 xenografts) compared with less aggressive AD cells (LNCaP and AD CWR22 xenografts). Furthermore, stable introduction of LMO2 into LNCaP cells conferred enhanced cell motility and invasiveness in vitro, accompanied by down-regulation of E-cadherin expression. Taken together, these findings provide the first evidence to support the hypothesis that LMO2 may play an important role in prostate cancer progression, possibly via repression of E-cadherin expression.