Ma’s Lab introduction

Ma laboratory established in 2010 and have focused on understanding the molecular mechanism of diseases biology and applying in clinical diagnosis and therapy. In the past years, we have successfully established a platform for systematic signaling screening in my laboratory. With this powerful tool in hand, we are (1) searching significant miRNAs as possible biomarkers or therapeutic targets for diseases, and (2) dissecting molecular mechanism of how Chinese herbs attenuates side effects of chemotherapy. Currently, my laboratory screened out specific MAPK/ERK-related miRNAs and found that miR-596 and mir-524-5p modulates MAPK/ERK signaling and apoptosis pathway in melanoma (Liu et al., Journal of Investigative Dermatology, 2018 and Oncotarget 2014). Moreover, we found that the specific local Taiwanese herb can suppress inflammation and liver fibrosis in animal model and we further identify its molecular mechanism through STAT3, NF-kB and Wnt signalings (Lin et al., Scientific Reports, 2017 and Journal of Food And Drug Analysis, 2018). Besides, my laboratory actively involves in collaborating with well-established laboratories in Taiwan to expand the scope of our research and to learn from senior PIs. Significantly, thirteen collaborating studies have been published in 2012-2017.
Several research results regarding development miRNA biomarkers in body fluid and miRNA detection technologies started to get notice by several biotech companies. Several different patents applications (radiation therapy, chronic kidney disease, dialysis disease and EPS) and the technology transfer are in progress. Our novel findings will have the impact to the knowledge of translation research in disease and provide the bridge into clinical in the future.

We expect to extend the research results to clinical and application areas.

I. Mechanism of miRNAs in signaling pathways

In our current proposed model, when the miR-524-5p expression level and the activity of MAPK/ERK signaling reach a balance, the cells maintain a steady state (Figure A). Continuously highly activated MAPK/ERK signaling lowers the expression of miR-524-5p, rendering it unable to inhibit MAPK/ERK activity and causing the  cells to exhibit high proliferation and migration properties (Figure B). In contrast, miR-524-5p overexpression inhibits the expression level of BRAF and ERK2 and suppresses MAPK/ERK activity, leading to reduced cell proliferation and migration events (Figure C). Our finding suggests miR-524-5p is a tumor suppressor miRNA and may serve as a potent therapeutic candidate in melanoma treatment. The research has been published on Oncotarget in 2014. (Oncotarget. 2014 Oct 15;5(19):9444-59.)

miR-596 expression is lower in melanoma than in tissue nevi. In addition, the patients with low miR-596 expression had significantly shorter overall survival than those in the high expression group (Figure a).  In addition, overexpression of miR-596 in melanoma cells significantly suppressed MAPK/ERK activity by targeting MEK1 mRNA and enhanced apoptosis by targeting MCL1 and BCL2L1 mRNA (Figure b, c). This results suggested that miR-596 may be a potential therapeutic candidate for melanoma treatment. This research has been published in The Journal of investigative dermatology in 2017. (J Invest Dermatol. 2018 Apr;138(4):911-921.)

II. The anti-inflammation and liver protection mechanisms of Antrodia cinnamomea

Antrodia cinnamomea (AC; synonym: Antrodia camphorata) is a unique herb found in Taiwan, and it is used as a traditional medicine for immune modulation or liver protection.

Our results demonstrated that CCM111, an aqueous extract of Antrodia cinnamomea, significantly reduces the NF-κB and STAT3 signaling pathways by luciferase reporter assay. Moreover, CCM111 can reduce pro-inflammatory cytokines in LPS-induced murine macrophages. Our current proposed model suggests that inflammatory responses are triggered when LPS induces the activation of the TLR4/NF-κB pathways, which produce IL-6 to activate the STAT3 pathway (Figure. a). CCM111 inhibits the phosphorylation of STAT3, Tyk2 and the nuclear translocation of p65 to reduce inflammatory responses (Figure b). This research has been published in The Journal of Scientific Reports in 2017.(Sci Rep. 2017 Jul 7;7(1):4862.)

Liver fibrosis is a chronic liver disease caused by many stimulatory factors; the production of excessive extracellular matrix (ECM) proteins results in the formation of scar tissue that affects liver function and results in liver cirrhosis. During the progression of liver fibrosis, the activation of hepatic stellate cells (HSCs) plays a critical role in the excessive production of ECM proteins, including type I collagen, type III collagen and alpha-smooth muscle actin (α-SMA). Therefore, reducing the activation of HSCs, inducing the apoptosis of HSCs or decreasing the accumulation of ECM proteins are considered antifibrotic methods or methods that reverse liver fibrosis.

In this research, our study provided novel insight into the mechanism by which AC ameliorates liver fibrosis. Our results suggested that CCM111 reduces the activity of TGF-β signaling pathways through inhibiting the levels of phosphorylated Smad2 and Smad3 and reducing the expression of α-SMA, MMP2, and TGF-β1 in HSC-T6 cell lines. CCM111 also decreases CCl4-induced expression of ECM proteins by downregulating the activation of the TGF-β, Wnt, and STAT3 pathways and by reducing inflammatory responses. This results suggested that CCM111 might be a candidate for preventing and treating chronic fibrotic liver diseases. (This research has been submitted.)

III. The relationship between tumor resistance to radiation therapy and microRNA.

Radiotherapy, surgery and chemotherapy are the main methods of cancer treatment. Approximately 50% of all cancer patients will receive radiotherapy. However, many failures on radiotherapy remain unexplained for tumors with apparently similar size, stages, grades and delivered doses. It will be essential to assess deregulated signaling pathways and to develop agents inhibiting specific signaling pathways. In our laboratory, we use the plasma to investigate microRNAs associated with radiation resistance and to explore the mechanism of radiation resistance.

Patent in Taiwan (#106123853 approved), USA ( #15/691,730), China ( #201710581670.0).

IV. The exploration of microRNAs as biomarkers for urothelial carcinoma in patients with chronic kidney disease (CKD) and dialysis patients.

Urothelial carcinoma (UC) is the particular urological cancer types of bladder cancer in Taiwan. The previous data shows that the incidence of UC has highly correlation with CKD in Taiwan. Urine cytology and urinary cystoscopy are the leading clinical diagnosis method. However, urine cytology shows poor sensitivity in early stages. Therefore, highly sensitive, specific, noninvasive, and inexpensive UC screening marker would be helpful for CKD patients in Taiwan.

In this study, over 200 urine specimens were collected from hospital in Taiwan. One UC miRNA classifier can distinguish CKD and UC patients. We would like to apply this result to clinical screening for CKD patients, and bring more benefit to cancer patients in the future.