Blocking OLFM4/HIF-1α axis alleviates hypoxia-induced invasion, epithelial-mesenchymal transition, and chemotherapy resistance in non-small-cell lung cancer.

Hypoxia is a common biological hallmark of solid cancers, which has been proposed to be associated with oncogenesis and chemotherapy resistance. The purpose of the present study was to investigate the role and underlying mechanisms of olfactomedin 4 (OLFM4) in the hypoxia-induced invasion, epithelial-mesenchymal transition (EMT), and chemotherapy resistance of non-small-cell lung cancer (NSCLC). We observed dramatically upregulated expression of OLFM4 in several NSCLC cell lines, and this effect was more pronounced in A549 and H1299 cells. In addition, our data revealed that OLFM4 expression was remarkably increased in both A549 and H1299 cells under hypoxic microenvironment, accompanied by enhanced levels of hypoxia-inducible factor (HIF)-1α protein. The HIF-1α level was elevated in response to hypoxia, resulting in the regulation of OLFM4. Interestingly, OLFM4 was a positive regulator of hypoxia-driven HIF-1α production. Moreover, depletion of OLFM4 modulated multiple EMT-associated proteins, as evidenced by the enhanced E-cadherin levels along with the diminished expression of N-cadherin and vimentin in response to hypoxia, and thus blocked invasion ability of A549 and H1299 cells following exposure to hypoxia. Furthermore, ablation of OLFM4 accelerated the sensitivity of A549 cells to cisplatin under hypoxic conditions, implying that OLFM4 serves as a key regulator in chemotherapeutic resistance under hypoxia. In conclusion, OLFM4/HIF-1α axis might be a potential therapeutic strategy for NSCLC.

Clinicopathological analysis of the hydroa vacciniforme-like lymphoproliferative disorder with natural killer cell phenotype compared with cutaneous natural killer T-cell lymphoma.

Hydroa vacciniforme-like lymphoproliferative disorder (HVLPD) is defined as a distinctive clinicopathological type of cutaneous lymphoma and a subset of patients with this disease exhibit the natural killer (NK)-cell phenotype. The HVLPD-NK cell phenotype may be difficult to distinguish from cutaneous natural killer T-cell lymphoma (CNKTL), as these two diseases share similar immunophenotypic markers. Therefore, the aim of the present study was to analyze the clinicopathological features of this rare disease and compare these features with those of CNKTL. The clinical, histopathological and molecular features of 5 patients with the HVLPD-NK cell phenotype and 11 patients with CNKTL were evaluated. As well as certain subtle histopathological differences, there marked differences the age, distribution of lesions and clinical course differed between patients with these two diseases. These results suggest that the HVLPD-NK cell phenotype should be classified as a separate disorder and treated accordingly.

Prognostic significance of CD30 expression in nasal natural killer/T-cell lymphoma.

The present study aimed to investigate the expression of tumor necrosis factor receptor superfamily member 8 (CD30) in extranodal natural killer/T-cell lymphoma (ENKTL) using immunohistochemistry, and to evaluate the association between CD30 and clinicopathological and prognostic significance. CD30 expression was detected using immunohistochemistry on paraffin-embedded sections obtained from 122 patients with ENKTL prior to treatment. In total, 70 of these patients with complete clinical data were collected for prognostic analysis. The level of CD30 expression, of the 122 patients with ENKTL, was grouped on the basis of a 5-tiered scale as follows: 0%, no staining; 1+, <25% positive cells; 2+, 25-50% positive cells; 3+, 50-75% positive cells; and 4+, >75% positive cells). In total, 36 (29.5%) were classified as 0; 46 (37.7%) as 1+; 22 (18.0%) as 2+; 12 (9.8%) as 3+; and 6 (4.9%) as 4+. Among the 86 patients with scores between 1+ and 4+, the membranous staining patterns of CD30 expression were sporadic (33.7%), focal (43.2%), diffuse (15.1%) and angiocentric (8.1%). When considering a score of ≥3+ as CD30 positivity (CD30+), the CD30+ group had significantly shorter overall survival rates (P=0.0023) and progression-free survival rate (P=0.0008) compared with CD30 negative group. However, no statistically significant association was found between CD30 expression and clinicopathological features (P<0.05). The present study found that the expression of CD30 (≥3+) was significantly associated with poor prognosis but was not associated with clinical and histopathological parameters in ENKTL. Therefore, CD30 may be a useful prognostic marker in ENKTL.

Inhibitor of DNA binding 4 functions as a tumor suppressor and is targetable by 5-aza-2'-deoxycytosine with potential therapeutic significance in Burkitt's lymphoma.

Epigenetic gene silencing due to promoter methylation is observed in human neoplasia, including lymphoma and certain cancer types. One important target for gene methylation analysis in non-Hodgkin lymphoma (NHL) is inhibitor of DNA binding 4 (ID4). The present study aimed to investigate the gene methylation status of ID4, the expression of ID4 protein and the effect of demethylating agent 5-aza-2'-deoxycytosine (CdR) in the Raji human Burkitt's lymphoma cell line in vitro. Following assessment of the inhibition of Raji cell growth by various concentrations of CdR, the effects of CdR on the expression of ID4 protein were assessed using the immunocytochemical streptavidin-peroxidase method and semi-quantitative analysis, while apoptosis and cell cycle were determined by flow cytometry. The ID4 gene methylation status of Raji cells was tested using methylation-specific polymerase chain reaction analysis. ID4 was methylated and its protein expression was low in the control group, while ID4 was partly or completely demethylated and its protein expression was upregulated in Raji cells treated with CdR. In addition, CdR induced apoptosis and cell cycle arrest in Raji cells in a dose- and time-dependent manner. These results demonstrated that ID4 is hypermethylated and its protein expression is low in Burkitt's lymphoma cells, while CdR reversed the abnormal DNA methylation and induced re-expression of ID4 protein. Hypermethylation of ID4 promotes the proliferation of Burkitt's lymphoma cells; ID4 may function as a tumor suppressor and can be targeted with demethylating compounds such as CdR for the treatment of Burkitt's lymphoma.

Primary natural killer/T cell lymphoma of the cervix: case report and clinicopathological analysis.

OBJECTIVE: To present pathological and molecular characterizations of a rare case that was diagnosed as nasal-type natural killer (NK)/T cell lymphoma primarily arising in the cervix. CASE REPORT: An Asian woman was admitted to hospital with a hysteromyoma, and laparotomy was performed. A large tumor of the uterus was found, which was limited to the cervix. Pathological examination showed NK/T cell lymphoma, which was supported by histological and immunohistochemical studies and was confirmed by evidence of Epstein-Barr virus infection. Less commonly, this case concerned a cytotoxic T cell phenotype, as molecular studies showed evidence of a clonal T cell receptor γ chain gene rearrangement. Microscopically, prominent and extensive necrosis was the distinctive feature of this case, which reminded us of considering it as a tumor. CONCLUSION: Primary NK/T lymphoma of the cervix is rare. Our experience in this case provided variable information on both pathological and molecular studies. This case may be of value in the differential diagnosis of lymphoid lesions and other small cell tumors of the cervix.