Hepatocellular carcinoma (HCC) is one of the most predominant subjects of liver malignancies, which arouses global concern in the recent years. Advanced studies have found that Circular RNAs (circRNAs) are differentially expressed in HCC, with its regulatory capacity in HCC pathogenesis and metastasis. However, the underlying mechanism remains largely unknown. In this review, we summarized the functions and mechanisms of those aberrantly expressed circRNAs in HCC tissues. We hope to enlighten more comprehensive studies on the detailed mechanisms of circRNAs and explore their potential values in clinic applications. It revealed that hsa_circ_0004018 can be used as a potential biomarker in HCC diagnosis, with its superior sensitivity to alpha-fetoprotein (AFP). Notably, the correlation of circRNA abundance in the proliferation of liver regeneration (LR) has recently been clarified and different circRNA profiles served as candidates for nonalcoholic steatohepatitis (NASH) diagnosis also be discussed. Therefore, the improved understanding of circRNAs in HCC pathogenesis and metastasis proposed a novel basis for the early diagnosis in HCC patients, which provides a useful resource to explore the pathogenesis of HCC.

Transmembrane protein 88 (TMEM88), a newly discovered protein localized on the cell membrane.Recent studies showed that TMEM88 was involved in the regulation of several types of cancer.TMEM88 was expressed at significantly higher levels in breast cancer (BC) cell line than in normal breast cell line with co-localized with Dishevelled (DVL) in the cytoplasm of BC cell line. TMEM88 silencing in the ovarian cancer cell line CP70 resulted in significant upregulation of Wnt downstream genes (c-Myc, cyclin-D1) and other Wnt target genes including JUN, PTIX2, CTNNB1 (β-catenin), further supporting that TMEM88 inhibits canonical Wnt signaling pathway. Wnt signaling pathway has been known to play important roles in many diseases, especially in cancer. For instance, hepatocellular carcinoma (HCC) has become one of the most common tumors harboring mutations in the Wnt signaling pathway. As the inhibitor of Wnt signaling, TMEM88 has been considered to act as an oncogene or a tumor suppressor. Up-regulated TMEM88 or gene therapy approaches could be an effective therapeutic approach against tumor as TMEM88 inhibits Wnt signaling through direct interaction with DVL. Here, we review the current knowledge on the functional role and potential clinical application of TMEM88 in the control of various cancers. HighlightsWnt signaling displays an important role in several pathogenesis of cancer.Wnt signaling pathway is activated during cancer development.TMEM88 has an impact on cancer by inhibiting canonical Wnt signaling.We discuss the importance and new applications of TMEM88 in cancer therapy. K E Y W O R D Sβ-catenin, cancer, cancer therapy, TMEM88, Wnt signalling pathway Abbreviations: 1,25(OH)2D3, 1,25-Dihydroxyvitamin D3; AKT/mTOR, protein kinase B/the mammalian target of rapamycin; ATF2, Activating transcription factor 2; BC, breast cancer; CBE, clinical breast exam; CIZ1b, b-variant form of CIZ1; CK1, casein kinase 1; CRD, cystein-rich domain; CTNNB1, catenin β1; Dnmt3a, DNA (cytosine-5)-methyltransferase 3A; DVL, dishevelled; EMT, epithelial-mesenchymal transition; FAK, focal adhesion kinase; FZD, frizzled; GSK3β, glycogen synthase kinase 3β; HCC, hepatocellular carcinoma; HSCs, hematopoietic stem cells; IDCs, invasive ductal carcinomas; LC, lung cancer; LRP5, low density lipoprotein receptor-related protein-5; METTL13, methyltransferase like 13; MMP-7, matrix metalloproteinase-7; MRI, magnetic resonance imaging; NSCLC, nonsmall cell lung cancer; OC, ovarian cancer; P38, protein 38; PFS, progression-free survival; TCF/LEF, T cell factor/lymphoid enhancer factor; TCGA, the cancer genome atlas; TMEM88, transmembrane protein 88; TNBC, triple-negative breast cancer; VWV, Val-Trp-Val; Zo-1, tight junction protein 1.Yun-xuan Ge, Chang-hui Wang, and Fu-yong Hu have contribute equally to this work.

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Recent data have shown that Transmembrane protein 88 (TMEM88), a newly discovered protein localized on the cell membrane, interacts with the PDZ domain of disheveled-1 (Dvl-1) in Xenopus embryos. Indeed, TMEM88 might inhibit the canonical Wnt/β-catenin signaling pathway by competing with LRP5/6 for interaction with Dvl-1. TMEM88 plays a crucial role in regulating human stem cell differentiation and embryonic development. Until recently, the function of TMEM88 has been a matter of debate. In this study, we explore the role of TMEM88 in cytokine secretion and the role of the MAPK and Wnt/β-catenin signaling pathway in tumor necrosis factor-alpha (TNF-α)-induced TMEM88 expression in LX-2 cells. We demonstrated that overexpression of TMEM88 results in an upregulation of IL-6 and IL-1β secretion. On the other hand, knockdown of TMEM88 by transfecting siRNA decreased IL-6 and IL-1β secretion in LX-2 cells. Meanwhile, the results showed that TMEM88 silencing could increase the expression levels of canonical Wnt/β-catenin accompanied with upregulated phosphorylation of wnt3a, wnt10b and β-catenin protein levels in response to TNF-α. In conclusion, these results indicated that TMEM88 plays a significant role in TNF-α-enhanced cytokine (IL-6 and IL-1β) secretion of LX-2 cells via regulating JNK/P38 and canonical Wnt/β-catenin signaling pathway.