LAUSR

In the past few decades, hepatocellular carcinoma (HCC) has emerged as the most rapidly rising cause of cancer-related mortality in the USA [1]. Even though we are gradually getting a grip on the traditional risk factors of hepatitis C and B infections, the rising incidence of other risk factors such as alcohol-induced liver disease and non-alcoholic fatty liver disease (NAFLD) are posing continued challenges. Unfortunately, the 5-year survival rate remains dismal and is estimated to be only 18% [1]. This speaks of the lack of effective treatment options and highlights the importance of rigorous research efforts to discover and develop novel therapeutic strategies. The only curative treatment options today are liver transplantation, surgical resection, and ablation; but these cannot be offered to the majority of patients with HCC, as most patients typically present with advanced disease that is not amenable to these treatment modalities. Systemic therapies such as sorafenib, regorafenib, lenvatinib, and nivolumab are used when curative options cannot be offered; but are only modestly efficacious and ridden with numerous side effects. Hence, now more than ever, there is an acute need for efficacious therapies that focus on molecular and mechanistic targets in HCC. We know that HCC is a heterogenous cancer, with each individual tumor arising from a distinct genetic and molecular signature. Treatment of HCC thus requires recognition and targeting of specific signaling pathways which are central to the process of carcinogenesis. It has been previously well established that dysregulation of the Wnt/βcatenin signaling pathway plays a critical role in the development of HCC [2]. Among the multiple genetic and signaling alterations that can activate the Wnt signaling pathway, activating mutations in β-catenin gene CTNNB1, are the most common, ranging from 13 to 43% of all HCCs depending on the cohort being studied [3–5]. The β-catenin destruction complex is ineffective in phosphorylating and degrading β-catenin resulting in nuclear translocation of β-catenin [2]. In the nucleus, BCL9/BCL9L (B-cell lymphoma 9/B-cell lymphoma 9-like) and Pygopus act as transcriptional co-activators of β-catenin, and form a ‘Wnt enhanceosome’ along with T-cell factor-1/lymphoid enhancer factor-1 (TCF/LEF1) to drive the expression of downstream target genes. In light of this, Huge et al. present their findings describing an oncogenic role for BCL9 and BCL9L in HCC, with relevance to the Wnt-activation status of the cancer [6]. In their paper, Huge et al. first verify the relevance of BCL9 and BCL9L in human HCC by examining three separate publicly available HCC databases, TCGA-LIHC, GSE22058, and GSE25097, and demonstrating that BCL9 and BCL9L expression levels are significantly elevated in HCC tissue compared to adjacent non-HCC tissue in all three datasets. Previous studies have examined the role of BCL9 in cancer, including HCC [7–10]. Hyeon et al. [7] studied BCL9 in 288 primary HCC patients who underwent curative hepatectomy and noted that ~ 25% of the HCCs showed nuclear BCL9 protein expression. BCL9 expression correlated with increased microvascular invasion, increased intrahepatic metastasis, and higher Edmondson grade. More importantly, BCL9 appeared to be a marker of shorter disease-free survival after curative hepatectomy, but this trend did not reach significance (p = 0.078). Other studies have also shown similar findings, with inhibition of HCC migration, invasion and angiogenesis due to loss or downregulation in BCL9 [8, 10]. Huge’s group confirmed this finding to be true with regard to not only BCL9, but also BCL9L, * Satdarshan P. Monga [email protected]