Association of Mortalin (HSPA9) with Liver Cancer Metastasis and Prediction for Early Tumor Recurrence

Abstract

Hepatocellular carcinoma (HCC) is well known for poor prognosis and short survival because of high recurrence rate even after curative surgery. Today there is no available biomarker or biochemical test to indicate HCC recurrence, and this study aims to identify protein markers that can discriminate postoperative patients with early recurrence (ER), i.e. disease relapsed within the first year. In this study, 103 hepatitis B-related HCC patients were recruited, and 68 of them were used for ER-related biomarker discovery study. Proteomic expression patterns of matched tumor and adjacent non-tumor tissues from these patients plus 16 normal liver tissues were delineated by the two-dimensional gel electrophoresis differential profiling method. Significant protein spots were evaluated by hierarchical clustering analysis. SSP4612 that yielded the highest receiver operating characteristic (ROC) curve value for the ER subgroup of HCC was subsequently identified by tandem mass spectrometry, and the corresponding expression patterns were further confirmed by quantitative PCR, Western blot, and immunohistochemistry. Correlation analysis with clinicopathological data was also examined. Proteomic profiling analysis revealed overexpression of mortalin (gene HSPA9) in HCC when compared with the non-tumor and normal liver tissues (area under the curve (AUC) ‫؍‬ 0.821). Furthermore, elevated mortalin level was also detected in the ER subgroup of HCC versus the recurrence-free state (where no cancer recurs for >1 year) (AUC ‫؍‬ 0.833, sensitivity ‫؍‬ 90.9%, specificity ‫؍‬ 71.4%). Metastatic HCC cell lines also exhibited higher levels of mortalin and HSPA9 mRNA. Patients diagnosed with advanced tumor stages and neoplastic metastasis are usually untreatable and very often survive briefly. Liver cancer is one of the prevalent and lethal malignancies and represents a tumor type of highly invasive and aggressive behavior with ability to adapt to new environment. Because of its asymptomatic features during malignant progression, liver cancer is often diagnosed at very late stage when conventional and effective treatment options become unavailable (1).Hepatocellular carcinoma (HCC) 1 is the most common liver malignancy, accounting for the third most common cause of cancer-related deaths worldwide, especially in parts of Asia and Africa with estimated Ͼ680,000 new cases and half million of deaths annually (2, 3). Recent epidemiological studies have also projected an alarming increase of HCC in both Japan and the United States. The only curative treatments for HCC are surgical resection or liver transplantation (4, 5). To date, conventional chemotherapeutic regimen is ineffective against HCC with a response rate between 5-10%, and no single drug or "cocktail" could prolong the patient's survival. Even though after curative surgery, the long-term prognosis of HCC still remains poor, that is largely attributable to the high tumor recurrence rate (about 56% within the first year after surgery) (6).The current paradigm of HCC development is in...

Dickkopf 4 (DKK4) acts on Wnt/β-catenin pathway by influencing β-catenin in hepatocellular carcinoma

“…The relative mRNA expression was normalized using glyceraldehyde 3-phosphate dehydrogenase as an internal control. 2-(delta) (delta)Ct method was used to calculate the fold change in gene expression between HCC tissues and their corresponding nontumour liver tissues, as described previously (Yi et al, 2008). HCC tissue with DKK4 expression less than twofold of the non-tumour liver tissue was defined as negative for DKK4 expression (DKK4À), and those with more than twofold expression of the non-tumour liver tissue was defined as positive for DKK4 expression (DKK4 þ ).…”

“…Demographic data and clinicopathological features of the patients are summarized in Supplementary Table 2. Tissue samples were snap-frozen in liquid nitrogen immediately after resection and stored in À80 1C until used, as described previously (Yi et al, 2008).…”

Mortalin–p53 interaction in cancer cells is stress dependent and constitutes a selective target for cancer therapy

“…[16][17][18] Overexpression of mortalin was sufficient to increase the malignancy of breast cancer cells in both in vitro and in vivo models. The underlying mechanism was shown to be the sequestration of wild-type p53 in the cytoplasm, leading to inhibition of its transcriptional activation and control of centrosome duplication functions.…”

“…23 Similarly, mortalin-binding p53 peptides caused nuclear translocation and activation of p53. 19 Mortalin was identified as a marker for hepatocellular carcinoma (HCC) metastasis and recurrence by proteomics analysis of matched tumor and non-tumor tissues, 18 suggesting that it contributes to HCC development and recurrence.…”

Molecular Chaperones and Co-chaperones as Therapeutic Targets for Cancer

“…Over expression of Hsp70 was found to be responsible for resistance to cell death in pancreatic cancer [37]. Metastatic Hepatocellular Carcinoma cell lines have been reported to exhibit higher levels of Mortalin (mitochondrial Hsp70) and Mortalin-mRNA [38].…”