Abstract
Hepatocellular carcinoma (HCC) is among the most lethal cancers. Mounting studies highlighted the essential role of the HGF/c-MET axis in driving HCC tumor progression. Therefore, c-Met is a potential therapeutic target for HCC. However, several concerns remain unresolved in c-Met targeting. First, the status of active c-Met in HCC must be screened to determine patients suitable for therapy. Second, resistance and side effects have been observed frequently when using conventional c-Met inhibitors. Thus, a preclinical system for screening the status of c-Met signaling and identifying efficient and safe anti-HCC agents is urgently required. In this study, immunohistochemical staining of phosphorylated c-Met (Tyr1234) on tissue sections indicated that HCCs with positive c-Met signaling accounted for approximately 46% in 26 cases. Second, many patient-derived HCC cell lines were established and characterized according to motility and c-Met signaling status. Moreover, LZ8, a medicinal peptide purified from the herb Lingzhi, featuring immunomodulatory and anticancer properties, was capable of suppressing cell migration and slightly reducing the survival rate of both c-Met positive and negative HCCs, HCC372, and HCC329, respectively. LZ8 also suppressed the intrahepatic metastasis of HCC329 in SCID mice. On the molecular level, LZ8 suppressed the expression of c-Met and phosphorylation of c-Met, ERK and AKT in HCC372, and suppressed the phosphorylation of JNK, ERK, and AKT in HCC329. According to receptor array screening, the major receptor tyrosine kinase activated in HCC329 was found to be the epidermal growth factor receptor (EGFR). Moreover, tyrosine-phosphorylated EGFR (the active EGFR) was greatly suppressed in HCC329 by LZ8 treatment. In addition, LZ8 blocked HGF-induced cell migration and c-Met-dependent signaling in HepG2. In summary, we designed a preclinical trial using LZ8 to prevent the tumor progression of patient-derived HCCs with c-Met-positive or -negative signaling.
Highlights
Liver cancer is the sixth most common and third most deadly cancer worldwide [1]
Screening hepatocyte growth factor (HGF)/c-Met signaling in hepatocellular carcinomas
The phosphorylation of JNK can be markedly suppressed by the epidermal growth factor receptor (EGFR) inhibitor AG1478 (S3B Fig.). These results strongly suggested that JNK is downstream of EGFR in HCC329, and the EGFR-JNK axis is a promising target for LZ8 to suppress the tumor progression of this Hepatocellular carcinoma (HCC)
Summary
Hepatocellular carcinoma (HCC) is the most common type of liver cancer, accounting for 83% of all cases [2]. Diverse pathological mechanisms, such as hepatitis B and hepatitis C viral infection and alcohol or aflatoxin B1 exposure, trigger the development and progression of HCC [3]. The acquired resistance to and side effects from sorafenib have drawn attention [10]. An explanation for these drawbacks is the genetic heterogeneity of HCC that leads to the primary resistance to sorafenib. An effective therapy targeting the molecular pathway leading to the tumor metastasis of HCC has not been firmly established
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