Stathmin overexpression cooperates with p53 mutation and osteopontin overexpression, and is associated with tumour progression, early recurrence, and poor prognosis in hepatocellular carcinoma

Abstract

Stathmin, a major microtubule-depolymerizing protein, is involved in cell cycle progression and cell motility. This study aimed to elucidate its role in the progression, early tumour recurrence (ETR), and prognosis of hepatocellular carcinoma (HCC). Stathmin mRNA was overexpressed in 88/156 (56%) resected, unifocal, primary HCCs, while p53 mutation was present in 72 (46%) and osteopontin mRNA overexpression in 79 (51%). Stathmin mRNA expression exhibited high concordance (93%) with protein expression in 107 cases examined by immunohistochemistry. Stathmin overexpression correlated with high alpha-fetoprotein (>200 ng/ml, p = 0.02), larger tumour size (>5 cm, p = 0.012), high tumour grade (p < 0.0002), high tumour stage (stage IIIA-IV) with vascular invasion and various degrees of intrahepatic metastasis (p < 1 x 10(-8)), ETR (p = 0.003), and lower 5-year survival (p = 0.0007). Stathmin protein expression was often more intense in the peripheral regions of tumour trabeculae, tumour borders, and portal vein tumour thrombi. Stathmin overexpression correlated with p53 mutation (p = 0.017) and osteopontin overexpression (p = 1 x 10(-8)), both of which were associated with vascular invasion (both p < 0.0001) and poorer prognosis (p < 0.0004 and p = 0.0004, respectively). Regardless of the status of p53 mutation or osteopontin expression, stathmin overexpression was associated with higher vascular invasion (all p < 0.0001). Approximately 90% of HCCs harbouring stathmin overexpression with concomitant p53 mutation or osteopontin overexpression exhibited vascular invasion, and hence the lowest 5-year survival, p = 0.00018 and p = 0.0009, respectively. However, we did not find that stathmin overexpression exerted prognostic impact independent of tumour stage. In conclusion, stathmin expression correlates with metastatic potential, is an important prognostic factor for HCC, and may serve as a useful marker to predict ETR.

Overexpression of stathmin 1 is a poor prognostic biomarker in non-small cell lung cancer

“…More importantly, it was to note that STMN1 overexpression has been associated with poor survival of cancers, including colorectal cancer, hepatocellular carcinoma, and oral squamous-cell carcinoma. 5,9,13,14 We demonstrated that overexpression of STMN1 was an independent prognostic factor for survival in patients with NSCLC.…”

The overexpression of polycomb group proteins Bmi1 and EZH2 is associated with the progression and aggressive biological behavior of hepatocellular carcinoma

“…The aberrant expression of several molecules and the biological features involved in malignant transformation from dysplastic nodules to HCC have been reported, though the exact genetic mechanism remains to be explored. [23][24][25] Recently, several studies have also shown EZH2 to be highly expressed in aggressive tumors, including human breast cancer, prostate cancer and lymphomas. 9,[13][14][15]26,27 The present study showed PcG proteins Bmi1 and EZH2 which are epigenetic chromatin modifier involved in cancer development, 7 to be involved in this malignant progression of HCC.…”

Overexpression of far upstream element binding proteins: A mechanism regulating proliferation and migration in liver cancer cells

“…Especially in HCCs, elevated stathmin expression has been linked to increased tumor size, the presence of vascular invasion, intrahepatic metastasis, and decreased patient survival. 6 Microtubule destabilizing factors represent potential therapeutic target structures, because reduced but also increased stathmin bioavailability sensitizes tumor cells to treatment with chemotherapeutic agents. 4,7 So far, the regulation of stathmin has been attributed to the modulation of chromatin structure by enhancer of zeste homologue 2 (EZH2), 8 posttranscriptional silencing by the small noncoding RNA miR-223, 9 as well as the expression of the tumor suppressor gene p53.…”