Abstract
CTHRC1 expression is involved in invasion and metastasis in various tumors. However, the molecules involved in its signaling pathways in hepatocellular carcinoma (HCC) remain elusive. The migration and invasion abilities of HCC cells stably expressing CTHRC1 were assessed in vitro and in vivo with a mouse model. Moreover, signaling pathways involved in invasion and metastasis were analyzed. CTHRC1 was abundantly expressed in HCC cell lines and HCC tissues. CTHRC1 was also detectable in the serum of HCC patients, compared with non-tumor controls. CTHRC1 mRNA was positively correlated with large tumor size (p <0.003), Edmondson differentiation grade (p <0.0001), microvessel invasion (p <0.05), intrahepatic metastasis (p <0.005), and HCC stage (AJCC, p <0.0001). Ectopic expression of CTHRC1 in HepG2 cells promoted cell migration and invasiveness in vitro, and promoted tumor metastasis in a lung metastasis mouse model. Knockdown of CTHRC1 by short hairpin RNA (shRNA) in HCC cells suppressed migratory and invasive abilities. Growth factor-mediated CTHRC1 expression promoted cancer cell invasiveness and metastasis through activation of CREB/Snail signaling, which induced EMT change and MMPs expression. Therefore, CTHRC1 and its downstream molecules may be potential therapeutic targets for HCC invasion and metastasis.
Highlights
Hepatocellular carcinoma (HCC) is a fatal liver cancer and a leading cause of cancer mortality worldwide
We further statistically analyzed Collagen triple helix repeat containing-1 (CTHRC1) messenger RNA abundance with real-time RT-PCR in six relevant groups of samples: normal liver (NL), liver cirrhosis (LC), GI (Edmondson-Steiner grade I), GII, GIII, and GIV hepatocellular carcinoma (HCC) (Figure 1B)
CTHRC1 has shown to be abundantly expressed in human pancreatic cancer tissues [22], hepatocellular carcinoma [7], gastric cancer [23], colorectal cancer [24], and gastrointestinal stromal tumors [25]
Summary
Hepatocellular carcinoma (HCC) is a fatal liver cancer and a leading cause of cancer mortality worldwide. Overexpression of CTHRC1 in hepatocellular carcinoma contributes to tumor invasion and predicts worse prognosis [7]. To date, few www.impactjournals.com/oncotarget investigations have addressed the molecules involved in related signaling pathways, which promote HCC invasion and metastasis. Matrix metalloproteinases (MMPs) play a role in cancer cell migration [8, 9]. Secreted CTHRC1 overproduced in cancer cells may act on the surrounding microenvironment, such as stromal cells and ECM, to promote tumor invasion and metastasis. The functional role of CTHRC1 was investigated in HCC cell invasion and metastasis in vitro and in a mouse model, respectively. We found that growth factor-mediated CTHRC1 promoted invasion and metastasis in HCC cells through the PI3K/Akt/ CREB(Snail)/MMP signaling pathways
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