Omics characterization of HZE-induced hepatocellular carcinoma and development of a blood-based assay of circulating miRNA that may predict for hepatocellular carcinoma risk
Abstract
Our hypotheses are that HZE ion-induced and $\gamma$-ray-induced tumors arise by largely overlapping but not identical mechanisms, and that HZE ion-induced solid tumors are qualitatively different than spontaneous tumors of the same histiotypes. Furthermore, the differences may be evident early in tumorigenesis and can include enhanced malignancy. There are a number of assumptions underlying this model. One is that HZE ions induce tumors through the same mechanisms as low LET radiation, albeit more efficiently, which supports the use of RBEs to set quality factors. The second is that HZE ion-induced tumors are no more lethal than their spontaneous counterparts. This assumption is implicit in using incidence to mortality data from spontaneous tumors in risk estimation. Here we describe the examination of the first of these assumptions by comparing HZE ion (300 MeV/n 28Si)-induced hepatocellular carcinomas (HCC) to $\gamma$-ray (137Cs) or spontaneous HCC using "omics" approaches. The second assumption, equal malignancy of HZE ion-induced tumors and sporadic tumors appears to be incorrect for our HCC murine models. Here we describe the differences between HZE ion-induced, $\gamma$-ray-induced and spontaneous tumors that likely account for the differences in their malignancies and compare them with other murine models of HCC as well as with human HCC data. For example, there are clear differences in key HCC signaling pathways and pathways where metabolic and functional signaling seems very similar when comparing HZE-induced vs, $\gamma$-ray or spontaneous tumors. Interestingly, there appear to be significant differences in tumor infiltrating lymphocytes that suggest that HZE-induced tumors are immunogenically hidden as compared to $\gamma$-ray or spontaneous tumors. And, when compared to human HCC, HZE tumor gene expression profiles are associated with human genomics profiles from patients who are considered as poor responders to therapy. Biomarkers of radiogenic cancers, if they can be identified, will have a number of powerful uses in better understanding and protecting against cancer from space radiation exposures and possibly predict individual disease onset early in the oncogenic process. Monitoring cancer early detection biomarkers in space radiation exposed crewmembers could uncover incipient radiogenic cancers with the hope of reducing mortality. Towards this goal, circulating miRNA have been monitored at increasing times post-irradiation in an effort to identify biomarkers of HCC onset. Both C3H mice (HCC prone) and BALB/c mice (HCC resistant) were used. Twelve miRNA have been identified as elevated in the plasma of human HCC patients. Ten of those miRNA overlap with mouse miRNAs and are also elevated in the plasma of HCC-bearing C3H mice (BALB/c mice do not develop HCC). Of those 10 miRNA, four are elevated in C3H mice, and not in BALB/c mice, 6 months after HZE irradiation. HCC tumors are not evident for another 12-18 months suggesting their use as biomarkers of liver distress and HCC onset. Those putative miRNA biomarkers are now undergoing testing against F2 crosses of these two stains of mice that were also irradiated with 300 MeV 28Si.
- Publication:
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43rd COSPAR Scientific Assembly. Held 28 January - 4 February
- Pub Date:
- January 2021
- Bibcode:
- 2021cosp...43E1848S