Abstract
Background: With recorded under-performance of current standard therapeutic strategies as highlighted by high rates of post-treatment (resection or local ablation) recurrence, resistance to chemotherapy, poor overall survival, and an increasing global incidence, hepatocellular carcinoma (HCC) constitutes a medical challenge. Accumulating evidence implicates the presence of HCC stem cells (HCC-SCs) in HCC development, drug-resistance, recurrence, and progression. Therefore, treatment strategies targeting both HCC-SCs and non-CSCs are essential. Methods: Recently, there has been an increasing suggestion of MALAT1 oncogenic activity in HCC; however, its role in HCC stemness remains unexplored. Herein, we investigated the probable role of MALAT1 in the SCs-like phenotype of HCC and explored likely molecular mechanisms by which MALAT1 modulates HCC-SCs-like and metastatic phenotypes. Results: We showed that relative to normal, cirrhotic, or dysplastic liver conditions, MALAT1 was aberrantly expressed in HCC, similar to its overexpression in Huh7, Mahlavu, and SK-Hep1 HCC cells lines, compared to the normal liver cell line THLE-2. We also demonstrated a positive correlation between MALAT1 expression and poor cell differentiation status in HCC using RNAscope. Interestingly, we demonstrated that shRNA-mediated silencing of MALAT1 concomitantly downregulated the expression levels of β-catenin, Stat3, c-Myc, CK19, vimentin, and Twist1 proteins, inhibited HCC oncogenicity, and significantly suppressed the HCC-SCs-related dye-effluxing potential of HCC cells and reduced their ALDH-1 activity, partially due to inhibited MALAT1-β-catenin interaction. Additionally, using TOP/FOP (TCL/LEF-Firefly luciferase) Flash, RT-PCR, and western blot assays, we showed that silencing MALAT1 downregulates β-catenin expression, dysregulates the canonical Wnt signaling pathway, and consequently attenuates HCC tumorsphere formation efficiency, with concurrent reduction in CD133+ and CD90+ HCC cell population, and inhibits tumor growth in SK-Hep1-bearing mice. Conclusions: Taken together, our data indicate that MALAT1/Wnt is a targetable molecular candidate, and the therapeutic targeting of MALAT1/Wnt may constitute a novel promising anticancer strategy for HCC treatment.
Highlights
With recorded under-performance of current standard therapeutic strategies as highlighted by high rates of post-treatment recurrence, resistance to chemotherapy, poor overall survival, and an increasing global incidence, hepatocellular carcinoma (HCC) constitutes a medical challenge
We observed that the expression of Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was highest in HCC, compared to other pathological liver conditions or normal liver; compared to the normal liver samples, MALAT1 expression in the HCC and liver cell dysplasia samples was up-regulated by 3.23-fold (p = 1.38 × 10−6 ; t-test = 6.28), and 3.17-fold (p = 2.59 × 10−6 ; t-test = 6.28), respectively (Figure 1A)
Using different human HCC cell lines, we demonstrated that compared to its expression in the epitheloid well-differentiated Huh7 cell (1.5-fold, p < 0.01), the expression of MALAT1 was profoundly enhanced in the fibroblastoid poorly-differentiated Mahlavu (1.7-fold, p < 0.01) and HepG2 human hepatoblastoma cell lines (2.6-fold, p < 0.001), SK-Hep1 (2.8-fold, p < 0.001) HCC cell lines [14], and markedly low expression in the normal liver THLE-2 cell line (0.2-fold, p < 0.001) (Figure 1B)
Summary
With recorded under-performance of current standard therapeutic strategies as highlighted by high rates of post-treatment (resection or local ablation) recurrence, resistance to chemotherapy, poor overall survival, and an increasing global incidence, hepatocellular carcinoma (HCC) constitutes a medical challenge. As genome-wide analyses continue to reveal an increasingly broad landscape of functionally mutated non-coding transcriptomes, there is accruing evidence of the ‘driver’ role of the expression and/or activity of several lncRNAs in malignant transformation and oncogenic phenotypes [4]. This is consistent with common knowledge that lncRNAs, acting as cues for specific cellular states or bioactivities [5], may help identify cellular dysfunctions or pathologies such as malignancies, predict tumor behavior, provide prognostic insight, or inform anticancer therapeutic strategies [4,5]. It was suggested that increased expression of MALAT1 increased the proportion of pancreatic cancer stem cells (CSCs), decreased their sensitivity to anticancer drugs, enhanced their self-renewal capacity, accelerated their tumor angiogenesis, and promoted tumor growth [9], while the downregulation of MALAT1 promoted the proliferation of the glioma stem cell line SHG139S by suppressing the expression of stemness markers, Nestin and Sox2 [10]; the role of MALAT1 in the induction and/or maintenance of the CSCs-like phenotype in HCC remains unexplored, and there is a dearth of data detailing the role of MALAT1 in the maintenance and proliferation of CSCs in HCC.
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