Serum Sorbitol Dehydrogenase as a Novel Prognostic Factor for Hepatocellular Carcinoma after Surgical Resection
A large percentage of patients with hepatocellular carcinoma (HCC) who undergo surgical resection experience a recurrence of their disease. Therefore, predicting recurrence after resection for HCC is crucial to select appropriate surgical candidates. The aim of this study was to determine if serum sorbitol dehydrogenase (SORD) levels, an enzyme that reflects liver damage, was associated with the length of recurrence-free survival. This study’s findings that serum SORD levels ≥15 ng/mL were associated with a shorter recurrence-free survival might help to determine which patients are better candidates for surgery in HCC. Moreover, baseline serum SORD and alpha-fetoprotein (AFP) levels could better predict the outcome when used in combination, with patients having both elevated SORD (≥15 ng/mL) and AFP (≥400 ng/mL) levels having a particularly poor prognosis. Therefore, incorporating serum SORD along with AFP levels in clinical practice may raise predictability of prognosis in HCC patients.
大部分接受手术切除的肝细胞癌 (HCC) 患者会出现疾病复发。因此，预测 HCC 切除后的复发对于选择合适的手术候选者至关重要。本研究的目的是确定血清山梨醇脱氢酶 (SORD) 水平（一种反映肝损伤的酶）是否与无复发生存期的长度相关。本研究发现血清 SORD 水平≥15 ng/mL 与较短的无复发生存期相关，这可能有助于确定哪些患者更适合 HCC 手术。此外，当联合使用时，基线血清 SORD 和甲胎蛋白 (AFP) 水平可以更好地预测结果，SORD（≥15 ng/mL）和 AFP（≥400 ng/mL）水平升高的患者预后特别差。因此，在临床实践中结合血清 SORD 和 AFP 水平可能会提高 HCC 患者预后的可预测性。
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with a high prevalence and incidence in Asia . Liver resection is the treatment of choice for patients with early-stage or resectable HCC , but the results are unsatisfactory. The survival rate remains low for these patients due to the high recurrence rate. The 5-year recurrence rate was 68% in patients with a single HCC (≤2 cm) after hepatectomy , and HCC recurrence adversely affects the long-term survival of patients [4,5]. Therefore, predicting recurrence after resection for HCC is crucial in order to select appropriate surgical candidates. Previous studies have noted that preoperative serum alpha-fetoprotein (AFP) levels and various histological features of tumors such as tumor size and microvascular invasion are independent predictors of recurrence after resection [6,7,8,9,10,11,12]. However, histological features are limited since they cannot be evaluated preoperatively. Moreover, AFP has a relatively low sensitivity and specificity for accurately predicting HCC , and the association of AFP with surgical outcome has been contradictory [14,15]. As a result, there is still a need for a novel prognostic marker to predict outcomes in patients with HCC after resection.
Inflammation, necrosis, and liver regeneration induced by various liver diseases play an important role in promoting HCC development . More than 90% of HCCs develop in the context of hepatic damage and inflammation, making it a clear example of inflammation-related cancer. Sorbitol dehydrogenase (SORD), an enzyme in the polyol pathway converting sorbitol into fructose, reflects liver damage [17,18,19,20,21]. SORD is concentrated primarily in the liver similar to alanine aminotransferase (ALT) . In patients with liver diseases including hepatitis, cirrhosis, and HCC, serum levels of SORD are elevated along with elevated levels of serum aspartate aminotransferase (AST) and ALT [23,24].
The polyol pathway, which produces sugar alcohols by aldo-keto reductase and SORD contributes to cancer development and aggressiveness [25,26]. In the previous study, blood sugar alcohol levels such as sorbitol increased steadily from healthy controls to patients with chronic liver disease and finally, HCC patients . Moreover, increased expression of aldo-reductase and SORD was observed in various cancers such as liver, breast, and colorectal cancers [25,28]. A recent proteomics study found that the levels of SORD expression in tumor tissue were significantly associated with prognosis in patients with HCC [29,30], implying that serum SORD levels may be used as a prognostic marker in these patients. However, there has been no study evaluating the association between preoperative serum SORD levels and surgical outcomes of patients with HCC. This study aimed to evaluate the association between preoperative serum levels of SORD and HCC recurrence in patients with early-stage HCC after curative resection.
肝细胞癌 (HCC) 是最常见的原发性肝癌类型，在亚洲具有较高的患病率和发病率 [ 1 ]。肝切除是早期或可切除 HCC 患者的首选治疗方法 [ 2 ]，但效果并不理想。由于高复发率，这些患者的存活率仍然很低。肝切除术后单发 HCC（≤2 cm）患者的 5 年复发率为 68% [ 3 ]，HCC 复发对患者的长期生存产生不利影响 [ 4 , 5]。因此，预测 HCC 切除后的复发对于选择合适的手术候选者至关重要。先前的研究指出，术前血清甲胎蛋白 (AFP) 水平和肿瘤的各种组织学特征，如肿瘤大小和微血管侵犯是切除术后复发的独立预测因素 [ 6 , 7 , 8 , 9 , 10 , 11 , 12 ]。然而，组织学特征是有限的，因为它们无法在术前进行评估。此外，AFP 对准确预测 HCC 的敏感性和特异性相对较低 [ 13 ]，而 AFP 与手术结果的关联一直是矛盾的。14、15 ]。_ 因此，仍然需要一种新的预后标志物来预测 HCC 患者切除后的预后。
各种肝病引起的炎症、坏死和肝再生在促进HCC发展中发挥着重要作用[ 16 ]。超过 90% 的 HCC 在肝损伤和炎症的背景下发展，使其成为炎症相关癌症的明显例子。山梨醇脱氢酶 (SORD) 是多元醇途径中将山梨醇转化为果糖的一种酶，它反映了肝损伤 [ 17 , 18 , 19 , 20 , 21 ]。剑主要集中在肝脏中，类似于丙氨酸氨基转移酶（ALT）[ 22]。在肝炎、肝硬化和 HCC 等肝病患者中，SORD 的血清水平随着血清天冬氨酸氨基转移酶 (AST) 和 ALT 水平的升高而升高 [ 23 , 24 ]。
通过Aldo-Keto还原酶和SORD产生糖醇的多元醇途径有助于癌症发育和侵袭性[ 25,26 ]。在以前的研究中，山梨醇等血糖酒精水平稳定地从健康对照增加对慢性肝病的患者，最后，HCC患者[ 27 ]。此外，在各种癌症（如肝脏，乳腺和结肠直肠癌）中观察到aldo-yductase和Sord的表达增加[ 25,28 ]。最近的蛋白质组学研究发现，肿瘤组织中的SORD表达水平与HCC患者的预后显着相关[ 29,30]，这意味着血清 SORD 水平可用作这些患者的预后标志物。然而，尚无研究评估术前血清 SORD 水平与 HCC 患者手术结果之间的关系。本研究旨在评估治疗切除术后早期HCC患者术前血清和HCC复发性术前血清水平的关联。
In conclusion, a baseline, elevated preoperative serum SORD level (≥15 ng/mL) was significantly associated with poor prognosis in patients with HCC after curative-intend resection. Moreover, baseline serum SORD and AFP levels could better predict the outcome, with patients having both elevated SORD (≥15 ng/mL) and AFP (≥400 ng/mL) levels having a particularly poor prognosis. Based on these findings, incorporating serum SORD along with AFP levels in clinical practice may assist with decision-making regarding appropriate surgical candidates and avoiding unnecessary surgery in patients with an expected poor survival.
总之，基线、术前血清 SORD 水平升高（≥15 ng/mL）与 HCC 患者根治性切除术后预后不良显着相关。此外，基线血清 SORD 和 AFP 水平可以更好地预测结果，SORD（≥15 ng/mL）和 AFP（≥400 ng/mL）水平升高的患者预后特别差。基于这些发现，在临床实践中结合血清 SORD 和 AFP 水平可能有助于就合适的手术候选者做出决策，并避免对预期生存率较差的患者进行不必要的手术。
关键词： 肝细胞癌,无复发生存,山梨醇脱氢酶,hepatocellular carcinoma,recurrence-free survival,sorbitol dehydrogenase