Abstract
The R-spondin family plays important roles in embryonic development, including in humans. However, information on the relationship between R-spondin2 and hepatocellular carcinoma (HCC) is lacking. This study aimed was to explore the mechanisms of R-spondin2 action in the progression of HCC. By analyzing R-spondin2 expression levels in HCC tissues by IHC and database, we identified that HCC tissues had lower expression levels of R-spondin2, correlated with a poor prognosis. We also established R-spondin2-overexpressing and knockdown cell lines and measured their viabilities and invasion abilities in vitro and their oncogenic capacity in vivo. Human mRNA microarray analysis was performed to screen for mRNAs that were differentially expressed between R-spondin2-overexpressing and control HCC cells. Microarray and Western blot analyses showed significant changes in the MAPK signaling pathway after transfection. Furthermore, in vivo experiments indicated that R-spondin2 knockdown increased the tumorigenicity of HCC cells after subcutaneous implantation in mice. Altogether, our results indicate that the R-spondin2, which might be a novel tumor suppressor gene, were responsible for inhibiting the proliferation and invasion of HCC via the MAPK signaling pathway. IMPLICATIONS: R-spondin2 gene might be a novel tumor suppressor gene providing new clues to clarify the biological behavior of HCC and thus reduce patient mortality and prolong survival.
Highlights
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide, with high mortality and a low incidence of early diagnosis [1]
R-spondin2 was downregulated in HCC compared with corresponding nontumor liver (CNL) tissues
R-spondin2 expression levels in most CNL tissues were classified as þþ or þþþ, whereas levels in HCC tissues were À, þ, or þþ (Fig. 1A; paired t test, P < 0.01; Fig. 1B)
Summary
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide, with high mortality and a low incidence of early diagnosis [1]. Around 700,000 patients die from HCC or its related complications each year. China has a high incidence of HCC because of its high prevalence of HBV. Despite advances in diagnostic and surgical techniques, most patients with HCC are already at an advanced stage when diagnosed, missing the opportunity to undergo surgery. Even among patients able to undergo surgical resection, the 5-year survival rate is only 40% to 50%, and most eventually die from tumor recurrence and metastasis [3]. It is important to clarify the biological behavior of HCC to identify patients at high risk of recurrence and allow them to receive active treatment to prolong their survival
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