A role for Ubc9 in tumorigenesis.

The post-translational modifications ubiquitination and sumoylation have been implicated in regulating many critical cellular pathways. Like ubiquitination, sumoylation is a multistep process involving maturation, activation, conjugation and deconjugation. Ubc9 is a sole E2-conjugating enzyme essential for sumoylation. We have previously shown that alterations of Ubc9 expression affect tumor drug responsiveness. However, it is not clear whether there is any link between sumoylation and tumorigenesis, even though alterations of the ubiquitination pathway can lead to the development of cancer. In this study, we found that Ubc9 expression levels were elevated in ovarian tumors compared to the matched normal ovarian specimens, suggesting that Ubc9 may play a role in tumorigenesis. To test this, we overexpressed a dominant-negative mutant of Ubc9 (Ubc9-DN) and wild-type Ubc9 (Ubc9-WT) in the MCF-7 human breast tumor cells. Inoculating these cells as xenografts in mice revealed that tumors expressing Ubc9-WT grew better than the vector control, while tumors expressing Ubc9-DN exhibited reduced growth. This pattern was also seen in these cells when grown in culture. To better understand the mechanism behind this observation, we profiled gene expressions in these cells by microarray analysis and found alterations in expression of the pro-oncogene bcl-2 in these Ubc9-DN- and Ubc9-WT-expressing cells. Consistent with the bcl-2 results, subsequent studies revealed a higher rate of apoptosis and poor survival for the MCF-7 cells expressing Ubc9-DN, which are associated with downregulation of bcl-2. Together, these results suggest a role for Ubc9 in tumorigenesis at least partially through regulation of bcl-2 expression.

Thick melanoma in the elderly.

The objective of this analysis is to ascertain the natural history of elderly patients greater than 65 years of age with thick melanoma (T4) who were treated with surgery only. Although there are multiple data on elderly patients, there is not a systematic review of survival in elderly patients over 65 years, and with our analysis we tried to enlighten this field in view especially of the growing population of the elderly in the United States. We retrospectively evaluated 112 patients with thick (> or = 4 mm) melanoma aged 65 or greater. Mean age was 73 years. Mean follow-up was 36 months. The overall survival (OS) and disease-free survival (DFS) were 69 and 52 months, respectively. Univariate analysis predicted worse OS and DFS when patients have positive lymph nodes, high mitotic rate, and increasing thickness. By multivariate analysis, lymph node status was most predictive of OS and DFS. Lymph node status is the most important prognostic factor in elderly patients with thick melanoma. Our analysis has shown that elderly patients that received no adjuvant treatment did significantly worse than the historical controls. Patients with nodal metastases are candidates for adjuvant therapy. Those without nodal disease constitute a favorable patient group and thus have much better prognosis and may not need adjuvant therapy. However, they must be closely monitored or enrolled in randomized trials. Thus, treatment for melanoma patients older than 65 should be as aggressive as in younger patients, and these patients should not be denied adjuvant treatment based on their age only.