SKIN 
 

March 2019     Volume 3  Issue 2 
 

Copyright 2018 The National Society for Cutaneous Medicine 144 

RISING DERM STARS® 
 

 
Cell Cycle Activators and Tumor Suppressors that Correlate with Melanoma 
Progression 
 
Michelle Min, MD1, Byungwoo Ryu, PhD, Rhoda Alani, MD 
 
1Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 
 

 
 
Background/Objectives: Melanoma 
accounts for the highest numbers of skin-
cancer related deaths, and incidence of 
cutaneous melanoma continues to rise.1 
Good prognosis is highly dependent on early 
detection and appropriate staging.2 In 
addition to our current clinical and histological 
prognostic indicators, there may be a role for 
gene expression biomarkers in 
complementing our current melanoma 
staging and tumor burden assessment.3  
 
In this study, we sought to evaluate the 
potential utility of melanoma progression-
associated genes as biomarkers for disease 
burden in human skin tissue samples. Based 
on previous microarray studies, primary 
genes of interest were HELLS, NCAPH, and 
SPINT2.4 HELLS and NCAPH have been 
shown to be cell cycle activators upregulated 
in aggressive metastatic tumor cell lines in 
comparison to less-aggressive primary tumor 
cell lines. SPINT2 has been implicated as a 
tumor suppressor gene in multiple cancers; 
its expression induces cell apoptosis and 
tumor suppression in vivo.  
 
Methods: After defining the panel of 
melanoma biomarkers to evaluate, we 
optimized a multiplex reaction to efficiently 
quantify RNA for our genes of interest from 
small quantities of tissue. Quantitative real-
time polymerase chain reaction (qRT-PCR) 

was performed to quantify and compare RNA 
levels in human skin tissue samples of nevi 
(n=12), primary melanoma (n=12), and 
metastatic melanoma (n=12). While NCAPH 
expression levels were difficult to measure 
due to minimal expression in human tissue, 
we were able to successfully quantify HELLS 
and SPINT2.    
 
Results: HELLS expression levels were 
remarkably higher in metastatic melanoma 
compared to benign nevi (p=0.02) and 
primary melanoma (p=0.05) (Figure 1A). 
Meanwhile, SPINT2 expression levels were 
almost nonexistent in metastatic skin 
samples; this was evident when comparing 
metastatic melanoma to nevi (p=0.03) and 
primary melanoma (p=0.03) (Figure 1B). 
There was no statistical difference between 
nevi and primary melanoma (p=0.11 for 
HELLS, p=0.31 for SPINT2).  
 
Conclusion: Our assay system proved 
sensitive in detecting differences in 
expression levels of HELLS and SPINT2 in 
metastatic melanoma compared to benign 
nevi and primary melanoma. Such novel 
biomarkers help us further understand the 
biology of melanoma, with potential clinical 
implications in prognosis, therapy, and 
detection of treatment response and tumor 
recurrence.   
 



SKIN 
 

March 2019     Volume 3  Issue 2 
 

Copyright 2018 The National Society for Cutaneous Medicine 145 

Figure 1. Statistical analysis shows HELLS is 
upregulated (A) while SPINT2 is 
downregulated (B) in metastastatic 
melanoma (MM) compared to benign nevi 
and primary melanoma (PM). 
 

 

References: 
1. Guy GP Jr, Thomas CC, Thompson T, 

Watson M, Massetti GM, Richardson LC; 
Centers for Disease Control and 
Prevention (CDC). Vital signs: 
melanoma incidence and mortality 
trends and projections - United States, 
1982-2030. MMWR Morb Mortal Wkly 
Rep. 2015 Jun 5;64(21):591-6. 

2. Schramm, S.J., Campain, A.E., Scolyer, 
R.A., Yang, Y.H., and Mann, G.J. Review 
and cross-validation of gene expression 
signatures and melanoma prognosis. J 
Invest Dermatol. 2012; 132: 274–283. 

3. Gershenwald JE, et al. Melanoma 
staging: Evidence-based changes in the 
American Joint Committee on Cancer 
eighth edition cancer staging manual. 
CA Cancer J Clin. 2017 Nov;67(6):472-
492. 

4. Ryu B, Kim DS, Deluca AM, Alani RM. 
Comprehensive expression profiling of 
tumor cell lines identifies molecular 
signatures of melanoma progression. 
PLoS One. 2007 Jul 4;2(7):e594.