Stathmin 1 is a biomarker for diagnosis of microvascular invasion to predict prognosis of early hepatocellular carcinoma

Yongchao Cai,Changcheng Liu,Yang Yang,Xicheng Wang,Yanxiang Song,Xiuhua Li,Haibin Zhang,Pu You,Yuying Gu,Xiaolan Mu,Yong Fu,Ting Fang,Zhiying He

doi:10.1038/s41419-022-04625-y

Abstract

Microvascular invasion (MVI) is presently evaluated as a high-risk factor to be directly relative to postoperative prognosis of hepatocellular carcinoma (HCC). Up to now, diagnosis of MVI mainly depends on the postoperative pathological analyses with H&E staining assay, based on numbers and distribution characteristics of MVI to classify the risk levels of MVI. However, such pathological analyses lack the specificity to discriminate MVI in HCC specimens, especially in complicated pathological tissues. In addition, the efficiency to precisely define stages of MVI is not satisfied. Thus, any biomarker for both conforming diagnosis of MVI and staging its levels will efficiently and effectively promote the prediction of early postoperative recurrence and metastasis for HCC. Through bioinformatics analysis and clinical sample verification, we discovered that Stathmin 1 (STMN1) gene was significantly up-regulated at the locations of MVI. Combining STMN1 immunostaining with classic H&E staining assays, we established a new protocol for MVI pathological diagnosis. Next, we found that the degrees of MVI risk could be graded according to expression levels of STMN1 for prognosis prediction on recurrence rates and overall survival in early HCC patients. STMN1 affected epithelial-mesenchymal transformation (EMT) of HCC cells by regulating the dynamic balance of microtubules through signaling of “STMN1-Microtubule-EMT” axis. Inhibition of STMN1 expression in HCC cells reduced their lung metastatic ability in recipients of mouse model, suggesting that STMN1 also could be a potential therapeutic target for inhibiting HCC metastasis. Therefore, we conclude that STMN1 has potentials for clinical applications as a biomarker for both pathological diagnosis and prognostic prediction, as well as a therapeutic target for HCC.

Highlights

Hepatocellular carcinoma (HCC) is one of the four most fatal cancers worldwide [1]
We directly find the clues from databases including HCC patients with macro- or micro-vascular invasion
The Stathmin 1 (STMN1)-diagnosed microscopic Vascular invasion (VI) (MVI) was wrapped in CD34+ vascular endothelial cells, indicating that STMN1 could be used as a specific marker to diagnose MVI

Summary

INTRODUCTION

Hepatocellular carcinoma (HCC) is one of the four most fatal cancers worldwide [1]. Only 5–10% of HCC patients can be treated through surgery, and over 70% of patients have recurred in 5 years after surgery, including two-thirds of them recurred within 2 years [2, 3]. In in order to predict prognostic risks of recurrence and metastasis, addition, the expression levels of STMN1 in MVI tissues were and to plan the therapeutic regimens for recurrence and significantly higher in regular tumor tissues (Fig. 2D). The result showed that STMN1 was the most stably up-regulated gene in HCC tumor low-STMN1 expression (n = 45); (3) and Mhigh-risk group was defined as score of 3–4, based on detections with MVI positive tissues among the total of 75 genes (p = 1.35e-7) (Fig. 1D).

DISCUSSION

Findings

MATERIAL AND METHODS