Recent attention has been paid to the prognostic ability and underlying molecular mechanisms of IL-17 producing cells to foster growth and progression of HCC [8, 14]. However, research defining the relationships of IL-17 receptor family members and HCC has lagged. In the present study, we observed various expression patterns of IL-17 receptor family members in HCC tissues using immunohistochemistry, which probably suggested their distinct biological effects on tumor growth. Among these receptors, expression levels of IL-17RE exhibited specificity in prognostic ability for dismal outcome of patients with HCC. Compared to low subgroup, patients with high-density of IL-17RE have shorter OS and TTR in both intratumoral and peritumoral tissues. Therefore, patients with high density of IL-17RE need a close monitoring. IL-17RE may provide us a novel prognosticator for poor outcome of HCC patients after surgery.
High expression of intratumoral IL-17 was also related to the prognosis of HCC patients in this cohort, which drove us to investigate its correlation with IL-17RE. Combination of intratumoral IL-17RE and IL-17 densities yielded better predictive performance than them alone. These findings indicated intratumoral IL-17RE and IL-17 may be involved in a fine-tuned collaborative action in the procession of HCC. Although IL-17RE is the least well characterized cytokine of the IL-17 receptor family cytokines, a recent study  reported that IL-17RE could form heterodimeric complex with IL-17RA participating in induction of proinflammatory cytokines and chemokines. We therefore assumed that intratumoral IL17RE had a high degree of functional overlap with IL-17 producing cells and was responsible for aggressiveness of HCC cells, at least in form of heterodimeric complex with IL-17RA. Importantly, we documented that combination of intratumoral IL-17 and IL-17RE densities were associated with HCC recurrences which can be divided into early recurrence (≤24 months), a true metastasis caused by dissemination of cancer cells, and late recurrence (>24 months) originating from de novo hepatocarcinogenesis . In this study, we proposed that IL-17 and IL-17RE orchestrated the protumor activities in the procession of HCC recurrence and progression due to the residual intrahepatic metastases as well as de novo cancer in the liver remnant.
In addition to the local immune response in liver tissue, expression levels of considerable soluble factors in circulation may reflect the systemic immune status of individuals with tumor and act as noninvasive markers for HCC screening and recurrence monitoring . So, we evaluated the serum levels of Th17 associated cytokines/inflammatory mediators and found higher levels of IL-6, -17RA, -22 and TNF-α in HCC than those in haemangioma, suggesting their potential value as monitoring indictors in HCC. During inflammatory response, TNF-α and IL-17 can act in a synergistic manner to sustain neutrophil recruitment . Recent evidence  found that IL-17 could enhance IL-6 production and subsequently promote tumor growth. On the other hand, IL-6 and IL-9 were critical initiators of Th17 differentiation and expansion which facilitate IL-17 secretion [29, 30]. Interestingly, IL-22 has already been identified as a coexpression cytokine with IL-17 in Th17 cells and cooperatively induced an innate immune response . Thus, we proposed that distinct expression levels of these cytokines may reflect their potential immune regulatory properties and synergistic interactions of cytokine networks in part via IL-17 signaling pathway. Moreover, the kinetics of cytokine products may serve as critical homeostatic factors in inflammatory “context” to determine the direction of tumor progression to some extent. In the present study, IL-17 expression level was not increased significantly. We speculated that compared with the circulating factors, fertile liver tissues (soil) endowed with abundant activated inflammatory/immune cells may play a more important role to determine IL-17 as a protumoral component. Obviously, numerous cytokines or growth factors involved in IL-17 pathway also need to be investigated such as IL-1, IL-23, TGF-β. In the absence of commercial human IL-17RE ELISA kit, we did not detect its expression in serum. Further study is required in our future research.
Despite several substantive studies [10, 17] have confirmed the crosstalk with several types of inflammatory/immune cells contributed to the protumor power of Th17 (a major source of IL-17), knowledge of their interaction in HCC is still incomplete. In a recent study , we demonstrated HSCs were the vital inflammatory cells involved in the recurrence of HCC and could produce cytokines (IL-6 and TNF-α) to create a cytokine milieu that benefited the expansion of human Th17 cells . Moreover, our recent gene expression profile of HSCs confirmed several IL-17 receptors (e.g. IL-17RA, RB and RE) were expressed in HSCs (data not shown). Inasmuch as the function of HSCs as liver-resident antigen-presenting cells , we identified the phenotypic features of IL-17 producing CD4+ T cells with the influence of HSCs in vitro. Interestingly, our present investigation provided evidence that secretions of activated human HSCs induced in vitro expansion of IL-17+ CD4+ T cells in HCC. In contrast, a recent data indicated suppressing Th17 differentiation by mouse HSCs . Several aspects may contribute to this discrepancy. The first could be the different species (human vs mouse). Second, we used conditioned medium of HSCs, not per se HSCs, in order to eliminate the effects of other T cells on HSCs and subsequently feedback responses. Third, activation of HSCs can led to the loss of retinoic acid (RA)  which has already been identified as a key regulator to inhibit the generation of Th17 . Therefore, absence of RA and in vitro activation made human HSCs appear to be fibroblast-like cells which were addressed to promote the expansion of Th17 . Most recently, we found TREM-1 was a pro-tumor gene in HSCs , however, two independent studies on human gene expression profile displayed its contradictory roles in development of T cells: enhancing Th1 priming in mature dendritic cells  and dampening Th1 and Th17 responses in monocytes . Therefore, the same gene in different cells appears to bias certain function toward an alternatively activated phenotype, suggesting the mechanistic complexity in signal integration of functional genes in various cells. A detailed understanding needs to be investigated.
In this study, we only studied some representative inflammatory mediators and the blood sample size was not large. Additionally, response to the stimulation of activated HSCs, the roles of memory and naïve CD4+ T cells in expansion of IL-17+ cells should be different. Various synergistic effects from other T cells or secretions in PBMC may participate in this process. We believe there are more linkages between activated HSCs, IL-17 and their receptors than what involved in this study. Therefore, extensive studies are needed in the future.