Loss of HES1 expression is associated with extracellular matrix remodeling and tumor immune suppression in KRAS mutant colon adenocarcinomas.

The loss of HES1, a canonical Notch signaling target, may cooperate with KRAS mutations to remodel the extracellular matrix and to suppress the anti-tumor immune response. While HES1 expression is normal in benign hyperplastic polyps and normal colon tissue, HES1 expression is often lost in sessile serrated adenomas/polyps (SSAs/SSPs) and colorectal cancers (CRCs) such as those right-sided CRCs that commonly harbor BRAF or KRAS mutations. To develop a deeper understanding of interaction between KRAS and HES1 in colorectal carcinogenesis, we selected microsatellite stable (MSS) and KRAS mutant or KRAS wild type CRCs that show aberrant expression of HES1 by immunohistochemistry. By comparing the transcriptional landscapes of microsatellite stable (MSS) CRCs with or without nuclear HES1 expression, we investigated differentially expressed genes and activated pathways. We identified pathways and markers in the extracellular matrix and immune microenvironment that are associated with mutations in KRAS. We found that loss of HES1 expression positively correlated with matrix remodeling and epithelial-mesenchymal transition but negatively correlated with tumor cell proliferation. Furthermore, loss of HES1 expression in KRAS mutant CRCs correlates with a higher M2 macrophage polarization and activation of IL6 and IL10 immunosuppressive signature. Identifying these HES1-related markers may be useful for prognosis stratification and developing treatment for KRAS-mutant CRCs.

Identification and Functional Evaluation of miR-4633-5p as a Biomarker and Tumor Suppressor in Metastatic Melanoma.

BACKGROUND/AIMS: Sinonasal mucosal melanoma (SMM) is a rare but extremely aggressive disease. Interestingly, however, as lethal as SMM, a few patients could survive for over 5 years without metastasis. However, biomarkers for metastatic SMM are lacking. METHODS: Laser-capture microdissection combined with microRNA microarray and RT-qPCR was performed in formalin-fixed paraffin-embedded tissue samples from SMM patients whose follow-up studies were carried out in parallel. In vitro cell proliferation and invasion assays, gelatin zymography, western blot analysis and RT-qPCR were performed in melanoma cell lines. RESULTS: In the discovery stage, miR-4633-5p expressed differentially in sinonasal mucosal melanoma patients with short and long disease-specific survival. Subsequent large-sample validation revealed that expression of miR-4633-5p was lower in metastatic SMM than in non-metastatic patients (P< 0.001). Moreover, miR-4633-5plow was able to identify metastatic SMM with specificity of 100% (5/5) and sensitivity of 87.5% (21/24). Multivariate analysis further pinpointed miR-4633-5p as an independent marker for metastasis (relative risk: 54.22, P< 0.001). In vitro, overexpression of miR-4633-5p suppressed the growth and invasiveness of melanoma cells through inhibiting activation of Akt pathway and secretion of MMP2, while knockdown of miR-4633-5p reversed the inhibitory effects. CONCLUSION: Our findings underpin miR-4633-5p as a predictive biomarker in metastatic SMM and a pivotal tumor suppressor that negatively regulates the invasive growth of melanoma cells. Quantitative detection of miR-4633-5p can diagnostically predict the risk of metastasis in SMM patients, which, in turn, may lead to more personalized treatment with better prognosis.

Expressions and clinical significance of HER4 and CD44 in sinonasal mucosal malignant melanoma.

Sinonasal mucosal malignant melanoma (SNMMM) is a rare disease. The aim of this study was to investigate the expressions of HER4 and CD44 in human SNMMM tissues and their relationship with the clinicopathological features and prognosis of patients. In total, 64 paraffin-embedded samples of SNMMM treated in our hospital from 29 December 1999 to 24 June 2011 were collected. HER4 and CD44 were detected in the tissues of SNMMM by immunohistochemistry. The differences in the HER4 and CD44 expressions in the tissues were evaluated and matched with clinicopathological parameters and the survival rate, respectively. The positive rates of the HER4 and CD44 expressions were 70.3 and 65.6%, respectively; the positive expression of HER4 was correlated with a positive expression of CD44 (P<0.05). The positive expression of HER4 was correlated with the prognosis of SNMMM patients (P<0.05). There was no significant correlation between a positive expression of CD44 and the prognosis of patients (P>0.05). The expressions of HER4 and CD44 were not significantly correlated with sex, age, pigment, tumor site, etc. (P>0.05). Our results further emphasize a correlation between HER4 and CD44 expressions in SNMMM tissues and point out that a positive HER4 expression might be an important factor in valuing the prognosis of patients with SNMMM.

Clonal and genetic relationship between individual components of mucoepidermoid carcinoma: X-chromosome inactivation assay and microsatellite analysis.

Mucoepidermoid carcinoma is a common salivary gland malignancy characterized by genetic heterogeneity as well as cellular diversity of its neoplastic components, which include mucinous cells, epidermoid cells and intermediate cells. The clonal and genetic relationship between each component has not been investigated before, and it is unclear whether these three phenotypically distinct components differ genetically. Each component from all 21 cases was precisely microdissected and examined by microsatellite loss of heterozygosity (LOH) analysis with a panel of 5 microsatellite markers: D2S125, D5S417, D6S297, D6S1577, and D11S1311. In addition, X-chromosome inactivation assay was performed in the components from 18 female cases. The number of microdissected components varied from 2 to 3 depending on the quantity of each cell subpopulation. Histopathological observation indicated that these three components shared an inseparable connection. Identical patterns of X-chromosome inactivation were shared among all the components in 9 of the 11 available informative cases. Of these 9 cases, 5 cases showed partially or totally discordant LOH patterns. Microsatellite analyses revealed discordant LOH patterns in 9 cases, 4 of which were corroborated to have identical X-chromosome inactivation patterns. Concordant LOH patterns were observed in all the components in 3 cases. These data suggest that heterologous components in most mucoepidermoid carcinomas are monoclonally originated. Individual components displayed identical and/or distinct LOH, implying that disparate genetic changes were implicated in the process of phenotypic divergence.

Clinicopathological Features and Prognosis of Sinonasal Mucosal Malignant Melanoma: A Retrospective Study of 83 Cases in a Chinese Population.

AIMS: Sinonasal mucosal malignant melanoma (SNMMM) is a rare disease. The aim of the present study was to describe its clinicopathological features and prognosis in a Chinese population. METHODS: Data on 83 SNMMM patients were collected and analyzed. A survival analysis was performed using the Kaplan-Meier method and a log-rank test. RESULTS: The most common presenting symptoms of SNMMM were nasal obstruction, epistaxis, and bloody rhinorrhea. Histopathologically, 38 cases (45.78%) were amelanotic. Five cell types (epithelioid, undifferentiated, plasmacytoid, spindle, and clear) were identified. Positive staining for human melanoma black-45 and Melan-A was diagnostic of SNMMM. Advanced age, multiple tumor sites, and amelanotic-type SNMMM indicated a worse outcome (p = 0.008, p = 0.009, and p = 0.013, respectively). Neither adjuvant therapy nor the tumor stage was associated with overall survival. CONCLUSIONS: SNMMM is an uncommon disease with atypical symptoms. Its histopathological appearance is variable, especially in the amelanotic type. Thus, immunohistochemistry is important in the diagnosis, and it should be performed according to the histology.

[Expression and prognostic value of MTDH, Bcl-2 and E-cadherin in sinonasal malignant mucosal melanoma].

OBJECTIVE: To study the expression and predictive value of MTDH, Bcl-2 and E-cadherin in sinonasal malignant mucosal melanoma (SNM). METHODS: Seventy-four formalin-fixed paraffin-embedded SNM specimens were subjected to immunohistochemical staining of MTDH, Bcl-2 and E-cadherin. Correlation between staining results and disease outcome was analyzed.SPSS 19.0 software was used to analyze the data. RESULTS: Positive staining of MTDH, Bcl-2 and E-cadherin was observed in 56/74 (75.7%), 18/74 (24.3%) and 21/74 (28.4%) cases, respectively. MTDH positive patients had higher metastatic rate than MTDH negative patients (67.9% vs. 33.3%, P=0.009, OR=2.037, 95% CI: 1.034-4.016). Negative Bcl-2 was correlated with worse overall survival time (HR=2.023, P=0.025). Expression of E-cadherin was adversely associated with expression of MTDH (r=-0.315, P=0.006). CONCLUSION: High MTDH expression and low Bcl-2 expression suggest poor prognosis of SNM, while the predictive value of E-cadherin needs further study.