**7. Acknowledgment**

I sincerely appreciate all the members of my laboratory who have worked on and are currently working on LAPTM4B for their valuable contributions, and I appreciate the work which has been done by other groups on this topic. These studies of LAPTM4B have been supported by grants from 211 and 985 Foundation of Peking University, National High-tech R&D Program (863 Program) (2006AA02A305), 248 major R&D program of Beijing (H020220020310), NNSFC (90408018) and the Creative Drugs Foundation from Beijing Fangzheng Group.

I would also like to sincerely thank Professor Da Long Ma and his Colleges who have given me great encourage and help, and Dr. Michael A. McNutt who has provided great help in use of the English language.

#### **8. References**

30 Hepatocellular Carcinoma – Basic Research

recurrence. Conversely, up-regulation of LAPTM4B-24, an truncated isoform that lacks a 91 amino acid sequence at the N-terminus of LAPTM4B-35, promotes apoptosis and autophagocytosis, and therefore plays an antagonistic role in hepatocarcinogenesis. Overall, these data provide new insight into genes and proteins that are potentially important in the pathogenesis of liver carcinoma. This harbors great potential for future application as novel biomarkers for cancer diagnostics, pathological grading, progression monitoring and prognosis, and as novel molecular targets providing new strategies for biotherapy and

Up-regulation of expression of the *LAPTM4B* gene and LAPTM4B-35 protein occur in a broad range of human solid cancers and are often associated with poor prognosis, indicating there is a common key role for this oncogentic gene and protein in cancer development.

Although *LAPTM4B* gene and the encoded LAPTM4B protein have been the subject of more than a decade of study, there are still important issues which remain to be resolved. These include (1) the underlying mechanism(s) responsible for up-regulation of the *LAPTM4B* gene and LAPTM4B-35 protein in neoplastic transformation; (2) the possibility LAPTM4B may be associated with cancer stem cells. Our previous studies indicate that LAPTM4B-35 over-expressing cancer cells possess characteristics typical of cancer stem cells, including apoptosis-resistance, unlimited renewal capacity, metastatic potential and multi-drug resistance. In addition, a study by Lee et al., (2010) suggests that LAPTM4B together with Gp49a, Sox4, and CD34 genes may be "stemness-related" genes in a primitive hematopoietic progenitor cell line EML, and this study demonstrates that these genes are preferentially expressed in hematopoietic stem cells and down-regulated in mature hematopoietic cells. Study of whether LAPTM4B-35 protein is a marker of cancer stem cells is therefore warranted; (3) as it has been shown in our study that LAPTM4B protein localizes at late endosomes, lysosomes, mitochondria, and the plasma membrane (unpublished data), it may be supposed that trafficking of LAPTM4B protein in cells would be very important for execution of its functions, thus it is worthwhile studying when and how LAPTM4B-35 and LAPTM4B-24 trafficking functions in normal cells and in cancer cells; (4) the detailed molecular mechanism for enhancing function of multi-drug resistance of p-gp (MDR1) by LAPTM4B-35 over-expression; (5) the underlying mechanism for metastasis promoted by LAPTM4B-35 over-expression; (6) the detailed molecular mechanism for signaling network activation by LAPTM4B-35 over-expression in HCC; (7) the sensitivity and specificity of LAPTM4B mRNA and LAPTM4B-35 protein as a marker for HCC diagnosis; (8) the underlying molecular mechanism for which targeted chemotherapy of small compounds

I sincerely appreciate all the members of my laboratory who have worked on and are currently working on LAPTM4B for their valuable contributions, and I appreciate the work which has been done by other groups on this topic. These studies of LAPTM4B have been supported by grants from 211 and 985 Foundation of Peking University, National High-tech R&D Program (863 Program) (2006AA02A305), 248 major R&D program of Beijing (H020220020310), NNSFC (90408018) and the Creative Drugs Foundation from Beijing

chemotherapy of HCC.

depends on LAPTM4B-35 over-expression.

**7. Acknowledgment** 

Fangzheng Group.


LAPTM4B: A Novel Diagnostic Biomarker and Therapeutic Target for Hepatocellular Carcinoma 33

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**2** 

**Novel Therapeutic Targets for** 

*School of Biomedical Sciences, Faculty of Medicine* 

Yangchao Chen and Chi Han Li

*The Chinese University of Hong Kong* 

*Hong Kong SAR* 

**Hepatocellular Carcinoma Treatment** 

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Surgery is a possible curative treatment, but most symptomatic HCC cases are in advanced stage where surgical resection is not possible. For this group of patients, the prognosis after any kind of therapy remains unsatisfactory due to high relapse rate (Llovet et al., 2003). Studies were rigorously conducted to tackle various obstacles in treating HCC, putting the focuses on targeting cancer cells that either disseminated from the tumor origin, or escaped from therapeutic effects. Recently, a multikinase inhibitor sorafenib was approved by FDA for the treatment of advanced HCC patients. It marks a major advance in the field as the first efficacious targeted therapy for HCC. The primary molecular targets of sorafenib include vascular endothelial factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR) and Raf (Wilhelm et al., 2004). Although it significantly prolongs both patient survival and the

Other HCC associated targets, such as epidermal growth factor (EGF) signaling (Hampton, 2007), telomerase (Djojosubroto et al., 2005) and cyclooxygenase (Márquez-Rosado et al, 2005), were studied intensively with regard to their therapeutic effects. However, the benefits are far from satisfactory, so there is still a need to identify new therapeutic targets. The exploration of new targets against HCC involves multiple disciplines including hepatology, oncology, pathology and molecular studies. Increasing number of therapeutic targets which play crucial roles in HCC were identified. Identification of new targets not only improves the current HCC therapeutic modality, but also drives a deeper understanding of HCC that allows personalized treatment in the future. In this chapter, we will briefly review the novel molecular and cellular players that contribute to HCC tumorigenesis and progression, and evaluate their potential as

The studies of sorafenib administration and other growth signaling inhibitors demonstrated the prowess of targeting growth signalings such as epidermal growth factor (EGF), VEGF and PDGF pathways. In HCC, many other growth signalings were identified that markedly contributes to tumorigenesis and pathogenesis. They include insulin-like growth factor

time to progression, its overall survival benefit is modest (Llovet et al., 2008).

**1. Introduction** 

additional therapeutic targets.

**2. Growth receptor signaling** 

