MK is detectable in various carcinomas such as breast, prostate, grastric, colon, hepatocellular and urinary bladder carcinomas, neuroblastoma, glioma and Wilms’ tumor, exhibiting a proto-oncogene function[ ^{3 4 5 6}]. However, its expression is low or undetectable in adult normal tissues. MK is deeply involved in cancer progression, onset of inflammatory diseases and repair of injured tissues. MK suppresses tumor growth both in vitro and in vivo and it is believed that MK is a new therapeutic target for curing tumors.

It is widely held that growth factor signaling is terminated by lysosomal degradation of its activated receptor and endocytosed growth factor is transported to lysosome. Nuclear targeting is another important pathway through which signals of growth factors are mediated. The nuclear targeting pathway is down-regulated by the proteasome system. Degradation of endocytosed MK is suppressed by both proteasome and lysosome inhibitors. By contrast, proteasome inhibitor rather than lysosome inhibitor accelerates the nuclear accumulation of MK. Expression vector of less signal sequence MK in cytosol, can be constructed because endocytosed MK may be translocated to cytosol from cellular compartments before entering nuclei. Cytosol-produced MK undergoes proteasomal degradation, accumulates in nuclei as endocytosed MK, and is polyubiquitinated with its nuclear accumulation increased by proteasome inhibitors. MK molecule can be further dissected by cytosol-produced MK to investigate its role in degradation and trafficking. The N terminal half-domain of MK is more significantly susceptible to proteasomal degradation, whereas the C terminal half-domain is sufficient to locate nuclei. These data highlight the desensitization of nuclear targeting by growth factor MK and indicate that the proteasome system plays a critical role in desensitization of nuclear targeting. MK is prone to proteasomal degradation[ ¹³]. Because “off” signaling is essential for life, it is reasonable that nuclear targeting growth factor MK is prone to degradation by proteasome (Figure 2).

Nuclei orchestrate the running of cells and is a highly dynamic organelle containing dynamic compartments created by relatively immobile binding or assembly sites[ ¹⁴]. In order to function properly, nuclei should rely on a constant flow of molecules between cytosol and nuclei. Many proteins can be translocated into nuclei by the presence of import signals such as nuclear localization signal or sequence (NLS) which can be specifically recognized by receptors on nuclear pore complex[ ¹⁵], or certain shuttling proteins such as nucleolin[ ¹⁶]. After transported into nuclei, proteins can be docked at different subnuclear compartments. In subnuclear structures such as nucleoli, proteins may accumulate in a steady-state compartment mediated by nucleolar localization sequence (NoLS) or domain which might interact with local high-affinity binding sites[ ¹⁷]. We have identified the conformational determinants for MK nuclear and nucleolar localization[ ¹⁸], showing that K79R81, K86K87, and C-terminal tail of MK constitute the nuclear localization determinant, and play an important role in nuclear localization.

At ultra-structure level, nucleoli include three components: fibrillar center (FC), dense fibrillar component (DFC), and granular component (GC)[ ^{19 20}]. Although MK tanslocated to nucleoli and accumulated in nucleoli, its exact location in nucleoli is still unclear. Immunogold-labeling electron microscopy shows that MK is mainly localized in GC, DFC and the border between DFC and FC (data unpublished). Because each component is corresponding to a special biological function, the nascent transcripts appear in the junction region between FC and DFC, accumulate in DFC and continue intranucleolar migration of rRNA towards GC[ ^{21 22}], suggesting that the role of MK in nucleoli may be related to the control of rRNA gene transcription, pre-rRNA processing, and nascent ribosome subunit assembly, the downstream elements to control cell proliferation.

MK is frequently over-expressed in most carcinomas[ ³⁰]. Serum and urinary MK levels are becoming prognostic and diagnostic markers of various tumors. Furthermore, MK demonstrates many activities that are significantly correlated to carcinogenesis, indicating that MK is a candidate target of therapy for carcinomas.

Anti-sense ODNs have a huge potential as agents to turn off the expression of specific proteins in vitro and in vivo. Indeed, anti-sense MK ODNs show anti-tumor activities in various carcinoma cells. Moreover, they also suppress the growth of pregrown tumors in nude mice via atelocollagen-mediated gene transfer, and exert their inhibitory effect on mitosis of cancer cells[ ^{31 32 33}]. Thus, abolition of MK production or disruption of its signaling pathway is a good treatment modality for human carcinomas.

Currently, studies on gene therapy for cancer are carried out. The most difficult aspect of developing an in vivo approach to cancer is correctly targeting cancer cells. Many vectors target tumors for gene delivery, including viral and synthetic vectors (liposome and emulsion), which show promise in targeting cancer cells. It is essential to use a strong and tissue-specific promoter region if a suicide gene is to be expressed selectively in cancer cells. Compared with cytomegalovirus (CMV) promoter, MK promoter exhibits a stronger expression in Wilms’ tumor cells than CMV promoter[ ³⁴]. Furthermore, adenovirus containing CMV promoter-thymidine kinase gene can cause severe side effect to liver, while the MK promoter-thymidine kinase gene does not have such a side effect. Therefore, a suicide gene under the control of MK promoter is a highly potential strategy for the treatment of carcinomas[ ³⁵].

MK is comparatively ubiquitous in many kinds of tumor, whereas its expression is usually low or undetectable in normal adult tissue. Serum MK levels are also elevated in patients with various carcinomas, such as gastric, colon, hepatocellular, and lung carcinomas[ ²⁷]. These observations indicate that MK should be considered indispensable to the development and enlargement of tumors. Further analyses of MK mechanisms related to carcinogenesis should shed light on therapies for tumors and cancers. To further establish blood MK as a tumor marker, prospective studies on blood levels and prognosis will provide useful information. Further study should focus on the application of MK in gene therapy for cancer.