Liver cancer has been become one of most severe cancers causing a large number population dead in the world . Although several therapies including chemotherapy, arterial embolization, surgical resection, and radiofrequency ablation have been developed to treat the diseases, while none of them is ideal due to native side effects . Especially, the pathogenesis of liver cancer is not yet completely understood. Non-invasive diagnosis for liver cancers is wanted due to conventional method such as liver biopsy may cause significant morbidity . In the present study, we first measured OLFM4 blood level in liver cancer patients and healthy controls, and mRNA expression in liver paracancerous and cancer tissues. It was found liver cancer patients had higher OLFM4 blood level, and liver cancer tissues had higher OLFM4 expression level than liver paracancerous tissues. ROC analysis indicated that OLFM4 had a high diagnostic value for liver cancer. OLFM4 had a strong correlation to tumor size. Last but not least, we confirmed that OLFM4 contributed to liver cancer cell proliferation in HepG2 cells, and HIF-1α involves in regulation of OLFM4 on liver cancer cell proliferation.
Incidence of cancers is often different in different gender. For example, it was found that gender differences existed in cancer-associated venous thromboembolism . Yang et al found that females and males had different colorectal cancer survival . In lung cancer, it was found that long-time survival post curative resection in early stage non-small-cell lung cancer in women is better than in men, and women showed often more molecular changes than men . However, in our study, we did found gender differences for OLFM4 blood level and tumor size in liver cancer (Table 3). Whether gender is different in liver cancer needs further discussion since our number of patients in our cohort is limited.
Liver cancer has been found to induce the expression modification of a large body of genes. Zhang et al used bioinformatics analysis to identifying several key genes and pathways in hepatocellular carcinoma including GMPS, ACACA, ALB, TGFB1, KRAS, ERBB2, BCL2, EGFR, STAT3, and CD8A . Similarly, Shen et al also found the expression level of a panel of genes such as TOP2A, NDC80, FOXM1, HMMR, KNTC1, PTTG1, FEN1, RFC4, SMC4, and PRC1 was significantly changed in hepatocellular carcinoma . These genes might be potential non-invasive biomarkers for diagnosis of liver cancer. Pan et al found that SLC25A11 was downregulated in liver cancer compared to normal controls and low expression of SLC25A11 was significantly associated with clinical stage, vital status, histologic grade, overall survival (OS) and relapse-free survival (RFS), thus SLC25A11 may serve as a prognostic marker for liver cancer . OLFM4 is generally considered as a marker o stem cells. Interestingly, Suzuki et al found OLFM4 expression was associated with nodal metastases in esophageal adenocarcinoma, and might be an informative marker with the potential to improve preoperative assessment in patients with esophageal adenocarcinoma . Van der Flier found that OLFM4 was a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells . Myama et al found that OLFM4, LY6D and S100A7 could be potent markers for distant metastasis in estrogen receptor-positive breast carcinoma . Consistently, we found that blood level of OLFM4 was higher in liver cancer patients compared to healthy control, and mRNA expression was higher in liver cancer tissues than liver paracancerous tissues (Figs. 1 and 2). We also found that OLFM4 has a high predictive value for diagnosing liver cancer and closely correlated to tumor size (Figs. 3 and 4). However, Clemmensen et al analyzed the plasma levels of OLFM4 in normals and patients with gastrointestinal cancer, while there was no association being found between blood level of OLFM4 and colorectal malignancies . Therefore, OLFM4 might be potential non-invasive biomarkers for several cancer types including liver cancer, while more clinical and experimental data should be accumulated to further verify the predictive capacity for liver cancers.
Seeking a therapeutic target is very important for developing effective drugs to treat cancers. In the present study, it was found that OLFM4 promoted liver cancer cell proliferation (Fig. 5). In gastric cancer cells, it was found that depletion of OLFM4 gene inhibited cell growth and increased sensitization to hydrogen peroxide and TNFα induced apoptosis . Consistent with our results, Ashizawa et al reported that OLFM4 could activate STAT3 and affiliate tumor progression by decreasing expression level of GRIM19 in human hepatocellular carcinoma . Interestingly, Gao et al demonstrated that HIF-1α involved in the regulation of OLFM4 on hypoxia-induced invasion, epithelial-mesenchymal transition, and chemotherapy resistance in non-small-cell lung cancer . In the present study, we also confirmed that HIF-1α involved in the regulation of OLFM4 on liver cancer cell proliferation (Fig. 6). Thus, OLFM4/HIF-1α axis might be a target signaling pathway for developing novel drugs to treat liver cancer.
In summary, OLFM4 blood level is higher in liver cancer patients than in healthy individuals and mRNA expression level in liver cancer tissue than in liver paracancerous tissues. OLFM4 has high predictive capacity as a biomarker for liver cancer and closely correlated to tumor size. Importantly, it is confirmed that OLFM4 contributes to cancer cell proliferation, and HIF-1α involves in this activity. We believe that OLFM4/HIF-1α axis might be a target signaling pathway for developing novel drugs to treat liver cancer.