Pleomorphic adenoma gene 1 mediates the role of Karyopherin alpha 2 and has prognostic significance in hepatocellular carcinoma

Abstract

Background: Karyopherin alpha 2 (KPNA2) promotes tumor growth in hepatocellular carcinoma (HCC). We aimed to determine the content and clinical significance of mechanism underlying. Methods: The association of transcriptional factor pleomorphic adenoma gene 1 (PLAG1) with KPNA2 was explored by co-immunoprecipitation. In vitro gain-and loss-of-function models were established to explore the functional interaction. Clinical samples from 314 HCC patients were applied to explore the clinical significance. Results: We found that PLAG1 could associate with KPNA2 and be promoted into nucleus by KPNA2. The increment of proliferative and metastatic abilities by KPNA2 over-expression can be significantly retarded by PLAG1 inhibition. The co-enrichment of KPNA2 and PLAG1 in nucleus is observed in clinical samples and can distinguish patients with the worst prognosis. The positive PLAG1 expression is an independent risk factor of recurrence free survival (HR: 1.766, 1.315-2.371; P = 0.000) and overall survival (HR: 1.589, 1.138-2.220; P = 0.007). Especially for patients with positive KPNA2 staining (N = 152), the positive PLAG1 expression is the sole risk factor for both recurrence free survival (HR: 1.749, 1.146-2.670; P = 0.010) and overall survival (HR: 1.662, 1.007-2.744; P = 0.047).

Prognostic value of increased KPNA2 expression in some solid tumors: A systematic review and meta-analysis

“…First, KPNA2 might serve as a reliable prognostic marker for solid tumors. In this meta-analysis, we included fifteen different cancer types, including breast cancer [14–17], colorectal cancer [11–13], gastric cancer [10, 18, 19], prostate cancer [8], hepatocellular carcinoma [20, 21], epithelial ovarian carcinoma [4, 31], bladder cancer [27], esophageal squamous cell carcinoma [28], endometrial cancer [26], melanoma [30], OMGCT [25], upper tract urothelial carcinoma [29], meningioma [24], astrocytoma [23], head and neck squamous cell cancer [22]. The overall pooled results from these cancer types indicated that elevated KPNA2 expression was associated with patients' poor OS, TTR, RFS and PFS.…”

“…Meanwhile, it has been suggest that elevated KPNA2 could be associated with poor prognosis in a variety of solid tumors, including colorectal cancer [11–13], breast cancer [14–17], gastric cancer [10, 18, 19] and hepatocellular carcinoma [20, 21]. Intriguingly, it was reported that low cytoplasmic and nuclear KPNA2 expression may also predict an adverse outcome in radiotherapy-treated head and neck squamous cell cancer [22].…”

Peer Review #1 of "Identification of key genes and long non-coding RNA associated ceRNA networks in hepatocellular carcinoma (v0.2)"

“…(Jiang et al 2014b) KPNA2 imparts proliferative and metastatic abilities to the HCC cells by aiding the entry of certain transcriptional factors, such as PLAG2, into the nucleus. (Hu et al 2014) MCM7 has been identified as a prognostic marker of HCC that promotes cell proliferation and tumorigenicity by suppressing cyclin D1 expression via the activation of the MAPK pathway. Through this mechanism, MCM7 initiates DNA replication, which is a key process in cell cycle progression.…”

Targeting nuclear transporters in cancer: Diagnostic, prognostic and therapeutic potential

“…Some malignancies have a high recurrence rate following therapeutic or surgical intervention and it is important to identify risk factors in these patients that might predict recurrence. KPNA2 expression has been identified as a marker of both early and more frequent recurrence in liver cancer while it is also a marker of PSA recurrence in prostate cancer . In meningioma, elevated KPNA2 and XPO1 expression was observed in recurrent tumours in comparison to primary tumours and this correlated with increased recurrence rates .…”