The Effects Of Hepatic Progenitor Activation On Pathological Subypte Transition In Patients With Hepatocellular Carcinoma

Part1Clinical factors associated with survival of patients with multiple hepatectomyBackground&Aims:Recurrence after hepatectomy is the main reason affecting the prognosis of hepatocellular carcinoma (HCC) patients. The probability of recurrence and metastasis varies among patients with similar clinical appearance and diagnosis. During recurrence, transition of the pathological subtype of the tumor could be observed, which indicated the significant tumor heterogeneity. However, the underlying mechanism remains unknown. Our study aimed to identify the clinical features and risk factors affecting survival and recurrence after hepatectomy and to lay the foundation for exploring the mechanism and making better prognosis.Methods:We retrospectively collected139patients with liver cancer undergoing several procedures. All the patients were diagnosed with liver cancer of HCC pathological subtype at the first surgery, and the tumor tissues in the subsequent surgeries were all obtained and the occurrence of pathological subtype transition were determined. Based on the transition of pathological subtype, the patients were divided into a pathological transition group (n=32) and a non-pathological transition group (n=107). Univariable and multivariate analyses were performed to find the risk factors affecting survival and recurrence, in order to explore their predicting-efficacy for the prognosis of HCC patients with several procedures.Results:Our study found that there was no significant difference in clinical characteristics between pathological transition group and non-pathological transition group, but5-year survival rate in the non-pathological transition group was higher than that in the pathological transition group (75.84%vs.51.32%, P=0.0069). With univariable and multivariate analyses, tumor pathological transition, NLR≥1.9, AFP≥400ng/mL, HbeAg positive, and tumor diameter≥5.3cm were the independent risk factors for patients survival. Ishak score≥7, HbeAg positive, cirrhosis, and DBIL≥7umol/L were the independent risk factors for recurrence. Higher tumor heterogeneity was found in the pathological transition group with stratified analysis. In the pathological transition group, tumor diameter≥5.3cm, serum AFP≥400ng/mL, and multiple tumors were the independent risk factors for patients survival.Conclusion:In the process of tumor recurrence, tumor pathological subtype transition can significantly affect patients’survival. Clinical characteristics of the tumor were similar between patients in the pathological transition group and in the non-pathological transition group. Part2Part2The effects of HP activation on pathological subtype transition and stem cell characteristics in hepatocellular carcinomaBackground and aim:In first part, we found that pathological subtype transition after recurrence could significantly affect patients survival, although the clinical characteristics were similar between the pathological subtype transition group and non-pathological subtype transition group. Furthermore, patients in pathological subtype transition group showed high tumor heterogeneity, and tumor diameter≥5.3cm, serum AFP≥400ng/mL, multiple tumors were the independent risk factors for patients survival. However, the underlying mechanism is still obscure. Our previous study also found that ductular reaction (DR) can reflect activation of hepatic progenitor (HP), and is associated with survival and recurrence of patients with combined Hepatocellular-Cholangiocarcinoma. Based on previous findings, in this part, we aim to explore whether HP activation is correlated with pathological subtype transition during tumor recurrence, and to explore the effect of HP activation on the alteration of stem marker expression as well as the underlying mechanism.Methods:DR status are detected by immunohistochemistry including K7DR and PIDR. The statistical analysis are used to analyze the correlation between DR and HP activation, the expression alteration of stem markers (Bmi-1, EpCAM) and EMT key indicator(Twist-1). The effects of different stem marker expression on survival and recurrence are also analyzed.Results:Our data showed that HP activation status and stem marker expression were significantly different between pathological subtype transition group and non-pathological subtype transition group. Pathological subtype transition group showed higher EPCAM and Bmi-1expression than non-pathological subtype transition group. With univariable and multivariate analysis, EPCAM positive and PIDR≥15%in the non-tumor tissue, and Twist-1expression in the tumor were the independent risk factors for patients survival, while PIDR≥15%in non-tumor tissue was the independent risk factors for patients recurrence in the pathological subtype transition group. Further analysis found that PIDR was significantly related with high stem marker expression in tumor and non-tumor tissues, including non-tumor PCNA-LIPeriportal hepatocytes expression, non-tumor EPCAM expression, tumor Bmi-1expression and tumor Twist-1expression.Conclusion:Pathological subtype transition was significantly associated with HP activation in the non-tumor tissue in the process of recurrence. PIDR activation in non-tumor tissue can influence the expression of stem marker Bmi-1, Twist-1in tumor tissue, which indicates that HP activation can exert influence from non-tumor to tumor tissue and EMT might be involved in this process.