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Huaier Inhibits Cancer Progression Correlated with the Mutated EGFR and Other Receptor Tyrosine Kinases (c-MET/erbB-2) by Down-Regulation of Multiple Signal Transduction Pathways

Author(s): Manami Tanaka, Tomoo Tanaka, Fei Teng, Hong Lin, Ning Li, Zhu Luo, Ding Wei, and Zhengxin Lu

Background: Clinical significance of anti-cancer effects of Huaier (Trametes robiniophila murr) has been emphasized recently [1-3]. We have already reported the successful Huaier therapy based on the individual genomic potential and miRNA-mediated transcription control [4-7]. In prostate cancer, Huaier also proved to have a significant efficacy on the prevention of cancer progression [6].

Objective: We have been initiating clinical research for thorough understanding of molecular basis of Huaier effects, which contributes to define the responsible molecules and biosystems not only for recovery, but also for prevention of cancer progression and tumorigenesis.

Methods: The peripheral blood samples from the volunteer patients were analyzed by total RNA and non-coding small RNA sequencing on BGISEQ-500 Platform [8, 9]. KEGG pathway classification was hired for the analysis of the obtained information in the present study (https://www.genome.jp/kegg/) [10].

Results: In the present study, we focused on the patient and her family correlated with the mutated EGFR [11] and other receptor tyrosine kinases (c-MET [12-14]/erbB-2 [15, 16]). At first, high ratio of SNP variants as A-G transitions (241,896 in total, 37.0%) and A-C transversions (43,213 in total, 6.5 %), with skipped-exon (51%), which influenced significant changes in transcriptional factors and corresponding gene expression in multiple signal transduction pathways. The ratio of alteration ranged from 10% to 30% of total number of transcripts, detected as a drastic down-regulation by Huaier administration. Although the patient was diagnosed as benign meningioma, there were no genomic alteration in RNA polymerase II and its subunits [17], but only quantitative down-regulation in the attached transcriptional factors were observed. Additional to the massive down-regulation in the multiple signaling pathways, we identified additional modifications in neural systems and protein/hormone signal transfer by genetic changes in neural transmitters SLC6A4 solute carrier family 6 member 4 [18], and PRNP (prion protein); CD230 [19]. These alterations were hereditary, familial events. Overall drastic modifications in signal transduction contributed to compensate the defected function by the mutation of EGFR and other receptor tyrosine kinases, related to all the basic mechanisms controlling cell growth, proliferation, metabolism and many other processes regulating a wide variety of cell communications. Huaier seemed to take part in the epigenetic post-transcriptional control for the prevention in carcinogenesis and tumorigenesis for whole family members.

Conclusion: The present study provided valuable example for compensation of defecting function by mutated EGFR and receptor tyrosine kinases. We identified hereditary gene expression alterations in EGFR (erbB1), c-MET, HER2/neu (erbB2), together with SLC6A4 solute carrier family 6 member 4 (Htt), and PRNP (prion protein); CD230, in the benign meningioma patient. These mutations were hereditary among family members. Huaier administration contributed the rescue of defected cell communication systems by massive down-regulation in a wide variety of signal transferring pathways. The mutation in transcripts remained even after 2 years of treatment. There are scarce medicine or candidate compounds for mutated EGFR and receptor tyrosine kinases yet, and Huaier is the one successful candidate to prevent carcinogenesis, tumorigenesis, and the other severe health problems correlated with the multiple mutations in those tyrosine kinase regulation systems. The epigenetic post-transcriptional regulation would decide the pathogenicity with hereditary mutations in these transcripts.

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