HCC is currently a globally recognized liver disease with strong metastases and poor diagnosis. In China, HCC is the second most common malignancy after stomach cancer[3]. Early radical resection is the most effective method of treating HCC, so early diagnosis becomes the key to early treatment. At present, the combination of AFP detection and imaging examination is used to make an early diagnosis of HCC. AFP is the first choice for HCC tumor markers, but there are certain limitations, about 30%-40% of HCC patients have negative AFP test results[20]. It makes AFP not an ideal indicator for early HCC screening. Therefore, early tumor markers for HCC are urgently needed.
CircRNAs are participated in the process of tumor diseases and the regulation of molecular mechanisms[21]. CircRNAs are newly discovered non-coding RNAs with a circular structure and strong stability. It can regulate gene expression or combine with RNA-related proteins to perform biological functions[9, 22]. Studies have shown that circRNAs are not affected by repeated freezing and thawing and degradation of RNA, and is biologically stable[7, 23]. CircRNAs may be a diagnostic marker for tumors.
In recent years, some research reports revealed that some circRNA can be used as markers for early tumor screening and prognostic evaluation[24, 25]. For example, Chen et al. [26]sequenced prostate cancer tissue and adjacent tissue, and found that 7232 circRNAs were associated with prostate cancer. They further verified that circCSNK1G3 accelerates the growth and proliferation of cancer cells through combining with miRNA181, and it is expected to be used as a marker for early screening of prostate cancer. Yin et al.[27] determined that 22 circRNAs were decreased and 19 circRNAs were creased by comparing the circRNA sequencing data of breast cancer and healthy people, and they speculated that hsa_circRNA_0001785 might be a biological marker of breast cancer by drawing the expression map of breast cancer. Although, the study of circRNAs in HCC remains in its initial stage, and studies have found that circ0001649 has a low level in HCC and inhibits the progression of HCC through multiple small RNA sponges[28]. circDYNC1H1 inhibits metastasis and proliferation of HCC cells via regulating the level of miR-140-5p [29]. In addition, circ_0005705 adsorbs miR-335 through sponge and further regulates MAPK1 expression, ultimately promoting HCC progression[30]. Circ_103809 inhibited proliferation and invasion of hepatoma cells via suppressing the level of miR-620[31]. Literature reported that CircRNA SMARCA5 can be used as a novel HCC biomarker[32]. Recently, basic experiments have confirmed that downregulation of hsa_circ_0097009 can inhibit HCC cells proliferation and invasion [19], but there are few clinical reports on the relationship between hsa_circ_0097009 and HCC. Therefore, this study included 30 pathologically diagnosed patients with HCC and 30 healthy people, detected plasma hsa_circ_0097009 expression of these subjects and explored its clinical significance in the diagnosis, treatment, prognosis of HCC. It’s found that the level of hsa_circ_0097009 in the plasma of HCC patients was markedly higher than that of healthy people, and its level was significantly correlated with tumor size and AFP. At the same time, we found that the level of hsa_circ_0097009 in the plasma of HCC patients was markedly lower than the preoperative level. Further ROC curves showed that the plasma hsa_circ_0097009 level could diagnose HCC with hepatitis B and healthy people. And it has good diagnostic value, including high specificity and moderate sensitivity. In addition, after 5-year follow-up of HCC patients, we also found that the OS time of HCC patients with high plasma hsa_circ_0097009 level was markedly shorter than that of patients with low level. This also suggests that hsa_circ_0097009 can be a biomarker for early diagnosis, treatment and prognosis evaluation of HCC.
Of course, this study still has limitations. First, the number of clinical samples was small, and studies with larger sample sizes are still needed to verify the function of plasma hsa_circ_0097009 as a novel diagnostic biomarker for HCC, and we will continue to enrich the data later. In addition, the specificity of this diagnostic model is low, and other molecules or detection methods will be combined to improve the specificity in the future. Due to the evolution of cancer, tumor heterogeneity and cell population heterogeneity in human samples are far beyond our imaginations, single-cell analysis methods are becoming increasingly important in elucidating the complexity of biology. No research on hsa_circ_0097009 in other human tissues has been found so far, and we will continue to explore hsa_circ_0097009 at the single-cell level to further reveal its role in HCC and other diseases. According to bioinformatics analysis, miR-1261, miR-873, miR-769-5p, miR-636, miR-568 and miR-182 may be potential targets of hsa_circ_0097009 (Fig. 4). This is consistent with the results of Ning et al. In addition, it was shown that hsa_circ_0097009 is involved in process of liver cancer via the circ0097009/miR-1261/SLC7A11 axis regulating ferroptosis[19]. These findings imply that hsa_circ_0097009 takes a key part in HCC by targeting miRNAs, which may provide new ideas and more in-depth research clues for studying the molecular regulatory role of hsa_circ_0097009 in HCC. However, the specific molecular mechanism remains unclear. We will further study its molecular mechanism in the future.
In conclusion, the hsa_circ_0097009 level is upregulated in the plasma of HCC patients and can be correlated with the occurrence, development and prognosis of HCC. This makes the hsa_circ_0097009 it to be a potential biomarker for diagnosing HCC and assessing its prognosis.