Leung Carmen Oi-ning, Wong Carmen Chak-lui, Fan Dorothy Ngo-yin, Kai Alan Ka-lun, Tung Edmund Kwok-kwan, Xu Iris Ming-jing, Ng Irene Oi-lin, Lo Regina Cheuk-lam
Department of Pathology, The University of Hong Kong, Hong Kong, China.
State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.
Oncotarget. 2015 May 10;6(13):10880-92. doi: 10.18632/oncotarget.3534.
Hepatocellular carcinoma (HCC) is characteristically one of the most rapidly proliferating tumors which outgrows functional blood supply and results in regional oxygen deprivation. Overexpression of PIM1, a serine/threonine kinase, has been identified recently in human cancers. Knowledge on PIM1 in HCC is however, scarce. By immunohistochemical analysis on 56 human primary HCC samples, we observed overexpression of PIM1 in 39% of the cases. In two independent cohorts of paired primary and extra-hepatic metastatic HCC tissues, PIM1 expression was higher (p=0.002) in the extra-hepatic metastatic HCC tissues as compared with the corresponding primary HCCs. PIM1 was markedly up-regulated in multiple HCC cell lines in hypoxic condition (1% O2) versus normoxia (20% O2). Silencing of PIM1 suppressed HCC cell invasion in vitro as compared to non-target control, and decreased HCC cell proliferation in vitro and tumor growth and metastatic potential in vivo. Knockdown of PIM1 significantly reduced glucose uptake by HCC cells and was associated with decreased levels of p-AKT and key molecules in the glycolytic pathway. Taken together, PIM1 is up-regulated by hypoxia in HCC and promotes tumor growth and metastasis through facilitating cancer cell glycolysis. Targeting PIM1 may have potential role in the management of HCC.
肝细胞癌（HCC）是典型的增殖速度最快的肿瘤之一，其生长超过功能性血供，导致局部缺氧。丝氨酸/苏氨酸激酶PIM1的过表达最近在人类癌症中被发现。然而，关于HCC中PIM1的知识却很匮乏。通过对56例人类原发性HCC样本进行免疫组织化学分析，我们观察到39%的病例中PIM1过表达。在两个独立的原发性和肝外转移性HCC组织配对队列中，与相应的原发性HCC相比，肝外转移性HCC组织中PIM1表达更高（p = 0.002）。在缺氧条件（1% O2）与常氧条件（20% O2）下，多种HCC细胞系中PIM1明显上调。与非靶向对照相比，沉默PIM1可抑制体外HCC细胞侵袭，并降低体外HCC细胞增殖以及体内肿瘤生长和转移潜能。敲低PIM1可显著降低HCC细胞的葡萄糖摄取，并与p-AKT水平降低以及糖酵解途径中的关键分子有关。综上所述，PIM1在HCC中因缺氧而上调，并通过促进癌细胞糖酵解来促进肿瘤生长和转移。靶向PIM1可能在HCC的治疗中具有潜在作用。
