Introduction A defining feature of

Introduction A defining feature of cancer cells is disruption of the normal controls of the cell cycle; a tumor suppressor or inhibitor may act by restricting progression of the cell cycle. P27 (also known as cyclin-dependent kinase inhibitor 1B, P27, or Kip1) is a putative cell-cycle inhibitor protein encoded by the gene CDKN1B. Research has shown that P27 is a tumor suppressor in humans, when located in the nucleus [1]. Specifically, P27 prevents cells from progressing beyond the Gap 1 (G1) phase of the GSK-LSD1 hydrochloride synthesis by restraining the activity of the cyclin E/CDK2 (cyclin-dependent kinase 2) complex [2]. The function of P27 is highly altered by binding to cyclin-CDK complexes or by subcellular localization, determined by its phosphorylation status [3]. Movement of P27 from the nucleus to the cytoplasm is associated with tumor invasiveness. Particular to the present study, low levels or absent P27 in tumor specimens of patients with intrahepatic cholangiocarcinoma (CCA) was an independent and significant marker of poor survival [4]. The signaling pathway PI3K/AKT (i.e., phosphoinositide 3-kinase/protein kinase B) has crucial roles in cell growth, cycle progression, survival, and apoptosis [5]. Activation of AKT, the downstream effector of PI3K, is associated with the downregulation of P27 and cell cycle progression [6]. In human CCA cells, AKT is required for cell growth that is dependent on cyclooxygenase 2 (COX2, or prostaglandin-endoperoxide synthase 2, PTGS2) [7]. However, the underlying molecular mechanisms controlling cell proliferation/inhibition by either AKT or P27 in the context of CCA remain unknown.
Methods
Results
Discussion An increasing number of studies have indicated that P27 has a complex role in tumor progression. Initially, P27 was discovered as a tumor-suppressor controlling the G1/S cell cycle checkpoint by binding to the cyclin E/CDK2 complex [10]. Later it was found that cytoplasmic sequestration of P27 had an oncogenic role, by promoting cell motility [3]. However, the role of P27 in cancer development has not been fully elucidated. P27 has been found to be functionally disrupted in many human cancers including breast, prostate, ovarian, and CCA [11]. Inactivation of P27 occurs either through decreased expression levels or phosphorylation-dependent export from the nucleus to the cytosol. The PI3K/AKT pathway is often aberrantly activated in cancers. The PI3K/AKT pathway alters P27 promoter transcription through AKT-dependent phosphorylation of the forkhead transcription factors AFX and FKHR [12,13]. AKT as a central component was reported previously to phosphorylate P27 directly at T157, T198, and S10 [14]. Phosphorylation at T157 mediates the coupling of P27 to 14-3-3 and retention of P27 in the cytoplasm of human malignant cells, allowing cell cycle progression [15,16]. T157 was reported to lie within the nuclear localization signal of P27 (aa153–166) [17]. In addition, phosphorylation within or near the nuclear localization signal was shown to inhibit nuclear import of other proteins, and the possibility cannot be excluded that other kinases phosphorylate T157 [18]. AKT is known to interact with other cell-cycle regulators such as p21 to induce p21 cytoplasmic relocalization and rescue cell-cycle G1 arrest [16]. Relocalization of P27 from the nucleus to the cytosol is a common event during tumor progression [16]. The PI3K/AKT pathway is involved in the control of cytoplasmic accumulation of P27 [17].
Conflict of interest
Acknowledgments This study was supported by the National Natural Science Foundation of China (No. 81270868, to X.X.)
Introduction Hepatocellular carcinoma (HCC) is one of the most common cancers, many therapeutic methods and drugs have been developed, but its five-year survival rate is only 30%–40% [1]. Many genes have been found to regulate HCC progression, for example, JARID2 promotes HCC invasion, epithelial-mesenchymal transition (EMT) and metastasis by inhibiting tumor suppressor PTEN and activating protein kinase B [2]. SOX12 promotes HCC metastasis by promoting Twist1 and FGFBP1 expression [3]. Glutaminase 2 (GLS2) inhibits HCC migration, invasion and lung metastasis by inhibiting Rac1 activity [4]. But there are many more genes required to be found to explore the mechanisms of HCC progression, they are helpful to develop new therapeutic targets.