Abstract: Objective:To investigate the expressions of hexokinase 2 (HK2) in tissues of hepatocellular carcinoma (HCC) and adjacent tissues, and its relationships with the clinicopathologic factors of HCC and prognosis of patients.
Methods:The retrospective cohort and casecontrol study was conducted. The clinicopathological data of 204 patients with HCC who were admitted to the First Affiliated Hospital of Fujian Medical University from August 2010 to January 2013 were collected. The expressions of HK2 in cancer tissues and adjacent tissues were detected using Western blot. Observation indicators: (1) the expressions of HK2 in cancer tissues and adjacent tissues; (2) relationship between the expression of HK2 in cancer tissues and clinicopathologic factors; (3) risk factors affecting tumor recurrence and metastasis after radical resection of HCC; (4) relationship between the expression of HK2 and prognosis of patients. Followup using outpatient examination and telephone interview was performed up to December 31, 2015. Imaging examination, laboratory examination and emission computed tomography (ECT) examination were applied to patients once every 2 months within 1 year postoperatively and once every 3 months after 1 year postoperatively. Suspected patients received enhanced scan of computed tomography (CT) and ultrasound examination for confirming intrahepatic and extrahepatic tumor recurrence and (or) metastasis. A specific time of tumor recurrence and (or) metastasis was done by imaging examination. Measurement data with skewed distribution were described as M (range) and comparison between groups was analyzed using the rank sum test. The relationship between the expression of HK2 and clinicopathologic factors was analyzed by the chisquare test. The univariate analysis and multivariate analysis were done using the COX regression model. The survival curve and survival rate were respectively drawn and calculated by the KaplanMeier method, and the Logrank test was used for survival analysis.
Results: (1) The expressions of HK2 in cancer tissues and adjacent tissues: results of Western blot test showed that relative expressions of HK2 in cancer tissues and adjacent tissues were 4.51 (range, 1.48-11.58) and 0.28 (range, 0.18-0.49), respectively, with a statistically significant difference (Z=-6.816, P<0.05). The relative expression of HK2 ≤4.51 and >4.51 was respectively set as low expression and high expression due to a median of relative expression of HK2 in cancer tissues of 4.51. (2) Relationship between the expression of HK2 in cancer tissues and clinicopathologic factors: asymptomatically physical findings and symptomatic findings were respectively detected in 49 and 53 patients with high expression of HK2 in cancer tissues. Tumor diameter ≤2 cm, 2 cm< tumor diameter ≤5 cm, 5 cm < tumor diameter ≤10 cm and tumor diameter > 10cm were respectively detected in 1, 14, 52 and 35 patients. Ninetyone patients had 1 tumor and 11 had more than or equal to 2 tumors. Fiftysix patients had vascular tumor thrombi under endoscopy and 46 didn't have vascular tumor thrombi under endoscopy. There were significant differences in above indicators (x²=5.090, 47.087, 5.082, 3.842, P<0.05). (3) Risk factors analysis affecting tumor recurrence and metastasis after radical resection of HCC: results of univariate analysis showed that finding mode, tumor diameter, tumor with capsule, postoperative pathological differentiation, vascular tumor thrombi under endoscopy, peak value of postoperative TBil and expression of HK2 were risk factors affecting rate of 2year tumor recurrence and metastasis after radical resection of HCC ［HR=1.663, 3.159, 1.516, 0.426, 2.705, 1.419, 2.786, 95% confidence interval (CI): 0.119-2.472, 2.105-4.740, 0.989-2.322, 0.260-0.698, 1.851-3.952, 0.951-2.117, 1.819-4.269, P<0.05］. Results of multivariate analysis showed that symptomatic findings, vascular tumor thrombi under endoscopy and high expression of HK2 were independent risk factors affecting rate of 2year tumor recurrence and metastasis after radical resection of HCC (HR=2.702, 2.117, 6.908, 95%CI: 1.417-5.151, 1.386-3.233, 3.920-12.174, P<0.05). (4) Relationship between the expression of HK2 and prognosis of patients: all the 204 patients were followed up for 23-64 months with a median time of 45 months. The 1, 3, 5year survival rates after radical resection of HCC were 88.0%, 71.9%, 52.6% in patients with low expression of HK2 and 79.6%, 50.2%, 30.3% in patients with high expression of HK2, respectively, with a significant difference in survival (x²=13.841, P<0.05).
Conclusion:The elevated expression of HK2 in tissues of HCC may be used as an effective molecular marker to predict tumor recurrence and metastasis after radical resection of HCC.