Assistant Professor, Epidemiology
School of Medicine

Cancer Epidemiology, cancer biology, melanoma drug resistance, melanoma risk factors, gender difference/gender disparity

Alternative SOM website including Teaching Classes

My current projects have two related areas: 1) the molecular epidemiology of melanoma and the sex disparity in melanoma development; and 2) searching for novel therapeutic agents for RAS and RAF inhibitors for melanoma treatment, potentially also for treating other cancer types.
Molecular epidemiology of melanoma
Melanoma gender disparity: Melanoma incidence rates continue to increase in the past decades. UV radiation is the only known major environmental risk factor. Young women are at higher risk than men of the same age, but the risk factors were largely attributed to their sun behavior in the past. Through a series of publications based on cancer registry databases and other datasets, we have demonstrated that sex plays an independent role (independent of UV exposure or behavior) in melanoma development. At younger age (younger than approximate menopause age) the female sex is an independent risk for melanoma (not their behavior, it is intrinsic pathophysiological factors); while at older age the female sex shows a protective function against UV exposure. A review manuscript is in preparation for proposing a novel bimodel mechanism of melanoma development based on sex and age ratios. These novel observation and hypothesis challenges the traditional view of melanoma risk and bring sex-related factors into the front play, i.e., how sex hormones or other related physiological factors contribute to melanoma risk or modify UV effect in melanoma development. Utilizing molecular evidence obtained in the lab (with careful selection of reagents, especially antibodies), we have discovered the short form of estrogen receptor alpha (ER?46) expressed in melanocytes and melanoma cells which clarifies much of the confusion of the role of estrogen in melanoma and established a base for our further investigation. We also found ARalpha was expressed in all melanoma cell lines examined. We have currently collected ~300 saliva samples from melanoma patients and healthy control subjects controls (IRB approved, enrollment ongoing), with detailed demographics information and melanoma risk information collected.
Precision Prevention of Melanoma: We have identified a RAC1 polymorphism that is associated with higher melanoma risk (publication #31). With our new bimodel we propose that melanomas diagnosed in different sex and at different age have different susceptible genetic background. Thus we proposed to use a genomics approach (several NIH databases which I have guaranteed access) to identify these different genetic factors. Meanwhile we continue to use case-control DNA samples (collected by Genes, environment and melanoma (GEM) study, a multi-center on-going collaborative efforts) to analyze functional association of melanoma with cSNPs in estrogen related pathways. We have identified several SNPs in IGF1 and ESR1 that showed a significant association with melanoma in a crude unadjusted analysis. If replicable this study should provide information for identifying high-risk individuals for melanoma prevention –which is termed “precision prevention”.
Novel therapeutic method development for melanoma
Redox biology based combination treatment method: My studies on redox biology of melanoma led to several invited reviews recently, and three book chapters. We have identified luteolin (a natural compound) as an effective synergistic compound with first in-line clinic drug BRAF inhibitor Plx4032 (Zelboraf or Vemurafenib). In vivo animal study showed this combination treatment not only extended the response period but also reduced cytotoxicity. Manuscript is under review. Lab evidence and computer docking have revealed that luteolin may directly targeting BRAF. I have recently been working with Professor David Van Vranken in Chemistry Department for making novel compounds based on in silica and in vitro analysis for developing a new class of BRAF inhibitors. Furthermore, this study showed that luteolin lowered IC 50 for Plx4032 in BRAF wild-type cells (which has no effective clinical treatment at the time) and the combination treatment also worked well in vivo for a BRAF wild-type cell line, hence the method has great potential to extend the targeted therapy drug Plx4032 to BRAF wild-type patients (it has only been used for BRAF mutant patients so far).
NOS1 inhibitors as melanoma therapeutic agents: this is a funded project (PI Dr. Richard Silverman) to study potentials of using synthesized NOS1 inhibitors to treat melanoma. NOS1 is over-expressed in melanoma samples and NOS1 inhibitors were screened for their activities in anti-proliferation of melanoma cell lines in vitro. Several compounds showed low micromolar range of IC50 (< 2 ?M) and has been tested in vivo (xenografted mouse model). One drug named HH044 (provided by Silverman) exhibited robust anti-melanoma activity in mice (much more effective than the current clinic drug Plx4032, data not published yet). We propose that this compound inhibits melanoma tumor growth via promoting CD8+ T cell infiltration (modulating immune response).
Cancer cell dormancy and cancer stem cells in melanoma
Cancer cell dormancy is an unsolved prominent issue as it is responsible for most treatment failures if not all. I accidently discovered a chemotherapy drug-induced dormant cell model which will enable us to collect large amount of dormant cells for identifying biomarkers and develop methods for preventing them from “waking up”. Gene expression profiling was completed and preliminary data analysis revealed that these dormant cells exhibit much cancer stem cell feature (molecular biomarkers) and showed a global chromatin remodeling characteristics as compared to the parental cells or G1 phase synchronized cells. Specifically we hypothesize that 4 ID genes (inhibitor of DNA binding, ID1-ID4) which are highly up-regulated in the non-dividing dormant cancer cells, play crucial roles of repressing regular proliferative activity by remodeling chromatin structure and suppressing key proliferative genes. These results are not published but should be at the leading edge of the research field and have great potentials to obtain extramural funding. The focus will be identification of biomarkers (ID proteins) in circulating blood from melanoma patients (my collaborator Dr. Jakowatz sees about 25 melanoma patients per week, many of these are returning patients, presumably carrying circulating cancer stem cells/dormant cells, therefore we should have sufficient supplies of blood sources), while understand the molecular mechanisms of why these cells stay in dormancy.
Our genomics profiling has also revealed several interesting factors: 1) these dormant cells switched their energy production from Warburg metabolism to mitochondria-mediated oxidative phosphorylation; 2) these dormant cancer cells utilize a combined molecular strategy to shut off their antigen-presenting function and thus evade immune surveillance, which explains why they can survive in the patients for many years during the long remission time.

1. Hui Li, Juan Liu, Hui Zhang, Yibin Zhang, Weihua Zhou, Xiaojuan Xiao, Shuming Sun, Bin Zhang, Mridul Roy, Hong Liu, Weihong Tan, Mao Ye, Jing Liu, Zi Wang1, Feng Liu-Smith, 2019. A novel aptamer LL4A specifically targets Vemurafenib-resistant melanoma through binding to the CD63 protein, J. Investigative Dermatology, in revision.

2. Tze-An Yuan, Yunxia Lu, Karen Edwards, James Jakowatz, Frank L. Meyskens and Feng Liu-Smith. 2019. Race-, Age-, and Anatomic Site-specific Gender Differences in Cutaneous Melanoma Suggest Differential Mechanisms of Early- and Late-Onset Melanoma. International J of Environmental Research and Public Health. In revision.

3. Arredondo, V.; Roa, D.; Yan, S.; Liu-Smith, F.; Van Vranken, D. (2019) Total Synthesis of (±)- Pestalachloride C and (±)-Pestalachloride D through a Biomimetic Knoevenagel/Hetero Diels-Alder Cascade Org. Lett. 21, in press.

4. Oxidative stress and antioxidants in the pathophysiology of malignant melanoma. Elena Obrador, Feng Liu-Smith, Ryan W. Dellinger, Frank L. Meyskens, and Jose M. Estrela. Invited review for Biol. Chemistry, 2018 Oct 31. pii: /j/bchm.ahead-of-print/hsz-2018-0327/hsz-2018-0327.xml. doi: 10.1515/hsz-2018-0327. [Epub ahead of print]

5. Tze-An Yuan, Yunxia Lu, Frank Meyskens and Feng Liu-Smith. 2018. Sex difference in anatomic site-specific cutaneous melanoma rates suggests pathophysiological mechanisms in addition to UV radiation. Cancer Causes & Control, 2018 May;29(4-5):405-415

6. Filipp, Fabian; Birlea, Stanca; Bosenberg, Marcus; Brash, Douglas; Cassidy, Pamela; Chen, Suzie; D'Orazio, John; Fujita, Mayumi; Goh, Boon-Kee; Herlyn, Meenhard; Hornyak, Thomas; Indra, Arup; Kumarasinghe, Prasad; Leachman, Sancy; Le Poole, Caroline; Lionel, Larue; Liu-Smith, Feng; Manga, Prashiela; Montoliu, Lluis; Norris, David; Shellman, Yiqun; Smalley, Keiran; Spritz, Richard; Sturm, Richard A.; Swetter, Susan; Terzian, Tamara; Wakamatsu, Kazumasa; Weber, Jeffrey; Box, Neil, 2018, Frontiers in Pigment Cell and Melanoma Research. Pigment Cell and Melanoma Research, 2018 Nov;31(6):728-735. doi: 10.1111/pcmr.12728. Epub 2018 Oct 3.
PMID: 30281213

7. Vivek Abraham, Ryan Dellinger, Angela Garcia, Feng Liu-Smith, Kristin Kelly, 2018. 12-hydroxyeicosatetraenoic acid (12-HETE) levels are increased in Actinic Keratoses (AK) and Squamous Cell Carcinoma (SCC). JAAD, 2018 Dec;79(6):1152-1153. PMID: 29902547

8. Feng Liu-Smith* and Argyrios Ziogas, An age-dependent interaction between sex and geographical UV index in melanoma risk. J Am Acad Dermatol, in press. Available online December, 2017: http://www.jaad.org/article/S0190-9622(17)32748-2/pdf (*corresponding author)

9. Tze-An Yuan, Frank L. Meyskens, Feng Liu-Smith*, 2018. A cancer registry-based analysis on the non-white populations reveals a critical role of the female sex in early-onset melanoma. Cancer Causes & Control, 29(4-5):405-415 (*corresponding author)

10. Helma Zecena, Daniel Tveit, Zi Wang, B.Sc. Ahmed Farhat, Parvita Panchal, Jing Liu, Simar Singh, Amandeep Sanghera, Ajay, Bainiwal, Shuan Y Teo, Frank L Meyskens, Feng Liu -Smith*; Fabian Volker Filipp*, 2018. Systems biology analysis of mitogen activated protein kinase inhibitor resistance in malignant melanoma, BMC Systems Biology 12:33 (*co-corresponding author)

11. Tze-An Yuan, Vandy Yourk, Ali M. Farhat, Argyrios Ziogas, Angela Garcia, Frank L. Meyskens Jr, Hoda Anton-Culver, Feng Liu-Smith, 2018. A Case-Control Study of the Genetic Variability in Reactive Oxygen Species-Metabolizing Enzymes in Melanoma Risk. International Journal of Molecular Science, 19(1):242-260. (*corresponding author)

12. Yonghong Li, Victor Pham, Michelle Bui, Liankun Song, Chunli Wu1, Arman Walia, Edward Uchio, Feng Smith-Liu, Xiaolin Zi. 2017. Rhodiola rosea L.: an herb with anti-stress, anti-aging and immunostimulating properties for cancer chemoprevention. Current Pharmacology Reports, Volume 3, Issue 6, pp 384-395

13. Meyskens FL Jr, Liu-Smith F, Redox-Redux and NADPH Oxidase (NOX): Even More Complicated than We Thought it Might Be. J Invest Dermatol. 2017 Jun;137(6):1208-1210.

14. Liu-Smith F*, Farhat Ahmed Majid, Arce Anthony, Ziogas Argyrios, Taylor Thomas, Wang Zi, Yourk Vandy, Liu Jing, Wu Jun, McEligot Archana J., Anton-Culver Hoda, and Meyskens Frank L.. Gender differences in the association between the incidence of cutaneous melanoma and geographic UV exposure. J Am Acad Dermatol. 2017 Mar;76(3):499-505. (*corresponding author)

15. Roy Mridul, Liang Long, Xiao Xiaojuan, Peng Yuanliang, Luo Yuhao, Zhou Weihua, Zhang Ji, Zhang Shuaishuai, Qiu Lugui, Liu Feng, Ye Mao, Zhou Wen, Liu Jing. Lycorine Downregulates HMGB1 to Inhibit Autophagy and Enhances Bortezomib Activity in Multiple Myeloma. 2016, Theranostics. 2016 Sep 24;6(12):2209-2224

16. Jia J, Li C, Luo S, Liu-Smith F, Yang J, Wang X, Wang N, Lai B, Lei T, Wang Q, et al. Yes-Associated Protein Contributes to the Development of Human Cutaneous Squamous Cell Carcinoma via Activation of RAS. J Invest Dermatol. 2016 Jun;136(6):1267-77. doi: 10.1016/j.jid.2016.02.005. Epub 2016 Feb 20. PubMed PMID: 26902922.

17. Liu-Smith F*, Meyskens FL. Molecular mechanisms of flavonoids in melanin synthesis and the potential for the prevention and treatment of melanoma. Mol Nutr Food Res. 2016 Jun;60(6):1264-74. doi: 10.1002/mnfr.201500822. Epub 2016 Mar 21. Review. PubMed PMID: 26865001; PubMed Central PMCID: PMC4900912. (*corresponding author)

18. Wang Z, Ma B, Li H, Xiao X, Zhou W, Liu F, Zhang B, Zhu M, Yang Q, Zeng Y, et al. Protein 4.1N acts as a potential tumor suppressor linking PP1 to JNK-c-Jun pathway regulation in NSCLC. Oncotarget. 2016 Jan 5;7(1):509-23. doi: 10.18632/oncotarget.6312. PubMed PMID: 26575790; PubMed Central PMCID: PMC4808014.

19. Liu-Smith F*, Poe C, Farmer PJ, and Meyskens FL, Jr. Amyloids, melanins and oxidative stress in melanomagenesis. Exp Dermatol March 2015; 24(3):171-4. (*corresponding author)

20. Yang Z, Yang S, Misner BJ, Liu-Smith F, and Meyskens FL. The role of APE/Ref-1 signaling pathway in hepatocellular carcinoma progression. Int J Oncol May 2014; 45(5):1820-8.

21. Liu-Smith F*, Dellinger R, and Meyskens FL, Jr. Updates of reactive oxygen species in melanoma etiology and progression. Arch Biochem Biophys 2014; 563:51-5. PMC4209333 (*corresponding author)

22. Dellinger RW, Liu-Smith F, and Meyskens FL, Jr. Continuing to illuminate the mechanisms underlying UV-mediated melanomagenesis. J Photochem Photobiol B 2014; 138:317-23. PMC4230791

23. Sun W, Zheng Y, Lu Z, Wang H, Feng Z, Wang J, Xiao S, Liu F, and Liu J. LL-37 attenuates inflammatory impairment via mTOR signaling-dependent mitochondrial protection. Int J Biochem Cell Biol 2014; 54:26-35.

24. Sun W, Zheng Y, Lu Z, Cui Y, Tian Q, Xiao S, Liu F, and Liu J. Overexpression of S100A7 protects LPS-induced mitochondrial dysfunction and stimulates IL-6 and IL-8 in HaCaT cells. PLoS One 2014; 9(3):e92927. PMC3966836

25. Qu X, Shen L, Zheng Y*, Cui Y, Feng Z, Liu F*, and Liu J. A signal transduction pathway from TGF-beta1 to SKP2 via Akt1 and c-Myc and its correlation with progression in human melanoma. J Invest Dermatol 2014; 134(1):159-67. (*co-corresponding author)

26. Sun Z and Liu F*. Association of Nox1 and vinculin with colon cancer progression. Cancer Invest 2013; 31(4):273-8. (*corresponding author)

27. Liu F*, Bessonova L, Taylor TH, Ziogas A, Meyskens FL, Jr., and Anton-Culver H. A unique gender difference in early onset melanoma implies that in addition to ultraviolet light exposure other causative factors are important. Pigment Cell Melanoma Res 2013; 26(1):128-35. PMC4028153 (*corresponding author)

28. Krasieva TB, Stringari C, Liu F, Sun CH, Kong Y, Balu M, Meyskens FL, Gratton E, and Tromberg BJ. Two-photon excited fluorescence lifetime imaging and spectroscopy of melanins in vitro and in vivo. J Biomed Opt 2013; 18(3):31107. PMC3595716

2. Tze-An Yuan, Yunxia Lu, Karen Edwards, James Jakowatz, Frank L. Meyskens and Feng Liu-Smith. 2019. Race-, Age-, and Anatomic Site-specific Gender Differences in Cutaneous Melanoma Suggest Differential Mechanisms of Early- and Late-Onset Melanoma. International J of Environmental Research and Public Health. In revision.

29. Liu F*, Gomez Garcia AM, and Meyskens FL, Jr. NADPH oxidase 1 overexpression enhances invasion via matrix metalloproteinase-2 and epithelial-mesenchymal transition in melanoma cells. J Invest Dermatol 2012; 132(8):2033-41. (*corresponding author)

30. Liu F*, Singh A, Yang Z, Garcia A, Kong Y, and Meyskens FL, Jr. MiTF links Erk1/2 kinase and p21 CIP1/WAF1 activation after UVC radiation in normal human melanocytes and melanoma cells. Mol Cancer 2010; 9:214. PMC2928201 (*corresponding author)

31. Liu F*, Fu Y, and Meyskens FL, Jr. MiTF regulates cellular response to reactive oxygen species through transcriptional regulation of APE-1/Ref-1. J Invest Dermatol 2009; 129(2):422-31. PMC4321967 (*corresponding author)

32. Liu HL, Xu JJ, Dai XM, Shi JB, Xu S, Gao J, Yao QZ, and Liu F. Both DNA damage and mitochondrial dysfunction are involved in novel oxadiazolo[3,4-d]pyrimidine nucleoside derivatives-induced cancer cell death. J Appl Toxicol 2009; 29(6):489-95.

33. Yang Z, Yang S, Misner BJ, Chiu R, Liu F, and Meyskens FL, Jr. Nitric oxide initiates progression of human melanoma via a feedback loop mediated by apurinic/apyrimidinic endonuclease-1/redox factor-1, which is inhibited by resveratrol. Mol Cancer Ther 2008; 7(12):3751-60.

34. Tang Y, Simoneau AR, Liao WX, Yi G, Hope C, Liu F, Li S, Xie J, Holcombe RF, Jurnak FA, Mercola D, Hoang BH, and Zi X. WIF1, a Wnt pathway inhibitor, regulates SKP2 and c-myc expression leading to G1 arrest and growth inhibition of human invasive urinary bladder cancer cells. Mol Cancer Ther 2009; 8(2):458-68. PMC2768341

35. Liu F and Lee WH. CtIP activates its own and cyclin D1 promoters via the E2F/RB pathway during G1/S progression. Mol Cell Biol 2006; 26(8):3124-34. PMC1446954

36. Chen PL*, Liu F*, Cai S, Lin X, Li A, Chen Y, Gu B, Lee EY, and Lee WH. Inactivation of CtIP leads to early embryonic lethality mediated by G1 restraint and to tumorigenesis by haploid insufficiency. Mol Cell Biol 2005; 25(9):3535-42. PMC1084307 (*co-first author)

37. Qiu F, Guo L, Wen TJ, Liu F, Ashlock DA, and Schnable PS. DNA sequence-based "bar codes" for tracking the origins of expressed sequence tags from a maize cDNA library constructed using multiple mRNA sources. Plant Physiol 2003; 133(2):475-81. PMC523874

38. Cui X, Hsia AP, Liu F, Ashlock DA, Wise RP, and Schnable PS. Alternative transcription initiation sites and polyadenylation sites are recruited during Mu suppression at the rf2a locus of maize. Genetics 2003; 163(2):685-98. PMC1462470

39. Skibbe DS*, Liu F*, Wen TJ*, Yandeau MD, Cui X, Cao J, Simmons CR, and Schnable PS. Characterization of the aldehyde dehydrogenase gene families of Zea mays and Arabidopsis. Plant Mol Biol 2002; 48(5-6):751-64. (*co-first author)

40. Liu F and Schnable PS. Functional specialization of maize mitochondrial aldehyde dehydrogenases. Plant Physiol 2002; 130(4):1657-74. PMC166681

41. Liu F, Cui X, Horner HT, Weiner H, and Schnable PS. Mitochondrial aldehyde dehydrogenase activity is required for male fertility in maize. Plant Cell 2001; 13(5):1063-78. PMC135560

1. Hui Li, Juan Liu, Hui Zhang, Yibin Zhang, Weihua Zhou, Xiaojuan Xiao, Shuming Sun, Bin Zhang, Mridul Roy, Hong Liu, Weihong Tan, Mao Ye, Jing Liu, Zi Wang1, Feng Liu-Smith, 2019. A novel aptamer LL4A specifically targets Vemurafenib-resistant melanoma through binding to the CD63 protein, J. Investigative Dermatology, in revision.

NCI/NIH K07 (PI): Melanoma Risk: Interactions between UV radiation and NADPH Oxidase Gene family, 2013-2018

NIH, R01 (co-I): Selective Inhibition of Nitric Oxide Synthase for Multiple Indications.Aug 2015– July 2019

Melanoma Research Alliance, Young Investigator Award, PI, Molecular epidemiology on gender difference in early onset melanoma, 2017-2020

UCI-CFCCC and CSUF, the P20 Partnership for Cancer Health Disparities, PI, Epigenetic Mechanisms of Gender Disparities in Early Onset Melanoma, 2013-2015

American Association of Cancer Research

Pan-American Society for Pigment Cell Research (PASPCR)

Society for Melanoma Research (SMR)

Society of Free Radical Biology and Medicine (SFRBM)

American Society of Preventive Oncology (ASPO)

American Society of Clinical Oncology (ASCO)

Expert Witness
Melanoma cases and epidemiology 2017—2019

Epidemiology

Chao Family Comprehensive Cancer Center

Link to this profile
https://faculty.uci.edu/profile/?facultyId=6173

Last updated
03/04/2019