Jinping Lu

Cathepsins mediate tumor metastasis.

Cathepsins are highly expressed in various human cancers, associated with tumor metastasis. It is superfamily, concluding A, B, C, D, E, F, G, H, L, K, O, S, V, and W family members. As a group of lysosomal proteinases or endopeptidases, each member has a different function, playing different roles in distinct tumorigenic processes such as proliferation, angiogenesis, metastasis, and invasion. Cathepsins belong to a diverse number of enzyme subtypes, including cysteine proteases, serine proteases and aspartic proteases. The contribution of cathepsins to invasion in human cancers is well documented, although the precise mechanisms by which cathepsins exert their effects are still not clear. In the present review, the role of cathepsin family members in cancer is discussed.

N,N'-dinitrosopiperazine-mediated AGR2 is involved in metastasis of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) has a high metastatic character in the clinic, but its mechanism is not clear. As a carcinogen with organ specificity for the nasopharyngeal epithelium, N,N′-Dinitrosopiperazine (DNP) is involved in NPC metastasis. Herein, our data revealed that anterior gradient 2 (AGR2) was overexpressed in human NPC tissues, particularly in cervical lymph node metastatic NPC (LMNPC). High AGR2 expression was associated with NPC metastasis. Importantly, DNP induced AGR2 expression, and increased cell motility and invasion in the NPC cell line 6–10B. However, DNP-mediated cell motility and invasion was dramatically decreased when transfected with siRNA-AGR2. Further, AGR2 directly regulated cathepsin (CTS) B and D by binding them in vitro. These results indicate that DNP induces AGR2 expression, regulates CTSB and CTSD, increases cell motility and invasion, and promotes NPC tumor metastasis. Therefore, DNP-mediated AGR2 expression may be an important factor in prolific NPC metastasis.

c-Src activation promotes nasopharyngeal carcinoma metastasis by inducing the epithelial-mesenchymal transition via PI3K/Akt signaling pathway: A new and promising target for NPC

Aberrant activation of cellular Src (c-Src), a non-receptor tyrosine kinase, could promote cancer progression through activating its downstream signaling pathways. However, the roles of c-Src and phosphorylated-Src (p-Src) in nasopharyngeal carcinoma (NPC) progression are rarely investigated. Herein, we have identified high c-Src concentrations in the serum of NPC patients with distant metastasis using high-throughput protein microarrays. Levels of c-Src in serum and p-Src in human primary NPC samples were unfavorable independent prognostic factors for cancer-specific survival, disease-free survival, and distant metastasis-free survival. Depletion or inactivation of c-Src in NPC cells using sgRNA with CRISPR/Cas9 system or PP2 decreased cell viability, colony formation, migration and invasion in vitro and metastasis in vivo. In contrast, these malignancies could be up-regulated by overexpressed c-Src in a NPC cell line with low-metastasis potential. Furthermore, p-Src was involved in promoting NPC cell metastasis by inducing the epithelial-mesenchymal transition (EMT) process via activating the PI3K/Akt pathway and cytoskeleton remodeling. The p-Src-induced EMT process could be retarded by PP2, which mediated by down-regulating the PI3K/Akt pathway. In conclusion, elevated levels of c-Src in serum and p-Src in primary NPC tissue correlated with poor outcomes of NPC patients. And aberrant activation of c-Src facilitated NPC cells with malignant potential, especially metastasis ability, which mediated by the PI3K/Akt pathway activation and sequentially induced the EMT process. These findings unveiled a promising approach for targeted therapy of advanced NPC.

Clusterin induced by N,N'-Dinitrosopiperazine is involved in nasopharyngeal carcinoma metastasis

Nasopharyngeal carcinoma (NPC) has a high metastatic clinicopathological feature. As a carcinogen factor, N,N′-Dinitrosopiperazine (DNP) is involved in NPC metastasis, but its precise mechanism has not been fully elucidated. Herein, we showed that DNP promotes NPC metastasis through up-regulating anterior clusterin (CLU). DNP was found to increase CLU, matrix metalloproteinases (MMP) 9 and vascular endothelial growth factor (VEGF) expression and activity, further DNP-increased MMP-9 and VEGF expression was through up-regulating CLU. We also found that DNP increased the binding of CLU with MMP-9 or VEGF. DNP induced the motility and invasion of NPC cell, which was inhibited by siRNA-CLU. The clinical investigation showed that CLU, MMP-9 and VEGF were positively correlated with the tumor-node -metastasis (TNM) classification. These results indicate that DNP may promote NPC tumor metastasis through up-regulating CLU, MMP-9 and VEGF expression. Therefore, DNP-increased CLU expression may be an important factor of NPC-high metastasis, and CLU may serve as a biomarker for NPC metastasis.

Cdk3-promoted epithelial-mesenchymal transition through activating AP-1 is involved in colorectal cancer metastasis

Cyclin dependent kinase-3 (Cdk3) is a positive regulator of the G1 mammalian cell cycle phase. Cdk3 is involved in cancer progression, but very little is known about its mechanism in cancer development and progression. Herein, we found that Cdk3 increased colorectal cancer metastasis through promoting epithelial-mesenchymal transition (EMT) shift. Cdk3 was found to highly express in metastatic cancer and induce cell motility and invasion. Cdk3 was shown to phosphorylate c-Jun at Ser 63 and Ser 73 in vitro and ex vivo. Cdk3-phosphorylated c-Jun at Ser 63 and Ser 73 resulted in an increased AP-1 activity. Ectopic expression of Cdk3 promoted colorectal cancer from epithelial to mesenchymal transition conjugating AP-1 activation, while AP-1 inhibition dramatically decreased Cdk3-increased EMT shift. These results showed that the Cdk3/c-Jun signaling axis mediating epithelial-mesenchymal transition plays an important role in colorectal cancer metastasis.

Dinitrosopiperazine-decreased PKP3 through upregulating miR-149 participates in nasopharyngeal carcinoma metastasis

Nasopharyngeal carcinoma (NPC) has a high metastatic clinicopathological feature. As a carcinogen factor, N,N′‐dinitrosopiperazine (DNP) is involved in NPC metastasis, but its precise mechanism has not been fully elucidated. Herein, we showed that DNP promotes NPC metastasis through upregulating miR‐149. DNP was found to decrease Plakophilin3 (PKP3) expression, further DNP‐decreased PKP3 was verified to be through upregulating miR‐149. We also found that DNP induced proliferation, adhesion, migration and invasion of NPC cell, which was inhibited by miR‐149‐inhibitor. DNP may promote NPC metastasis through miR‐149‐decreased PKP3 expression. Therefore, DNP‐increased miR‐149 expression may be an important factor of NPC high metastasis, and miR‐149 may serve as a molecular target for anti‐metastasis therapy of NPC.

AGR2 diagnostic value in nasopharyngeal carcinoma prognosis

BACKGROUND Anterior Gradient (AGR) 2 concentration increases in the serum of tumor patients, and their diagnostic and prognostic significances were evaluated in some tumors. The previous works showed that AGR2 high express in nasopharyngeal carcinoma (NPC) biopsy tissues. However, whether AGR2 serves as a diagnostic and prognostic marker for NPC remains unclear. METHODS 42 healthy volunteers, 34 breast cancer patients and 124 NPC patients were enrolled into this study, and the serum samples were collected from these healthy volunteers, breast cancer patients and NPC patients. Concomitantly, 79 frozen nasopharyngeal specimens consisted of 65 NPC tissues and 14 normal nasopharyngeal tissues were enrolled in the observation. The enzyme linked immunosorbent assay (ELISA) was used to estimate AGR2 concentration in the serum samples, and AGR2 mRNA expressions in the frozen tissue samples were detected by real time RT-PCR. RESULTS The real time RT-PCR results showed that AGR2 mRNA level was increased in NPC tissues compared with the normal nasopharyngeal tissues (p<0.05). The ELISA data showed that AGR2 concentration in NPC serum was significantly higher in NPC patient serums than that in the health population (p<0.05). And, AGR2 expression showed a correlation with tumor node metastasis (TNM) grade (p<0.05) and Recurrence (p<0.05). Moreover, the cumulative survival rate of patients with high concentration of AGR2 was significantly lower than that of patients with low concentration of AGR2 (p<0.05), and the cumulative hazard rate of patients with high concentration of AGR2 was significantly higher than that with low concentration of AGR2 (p<0.05). CONCLUSION Serum AGR2 can be used as a serum marker for clinical prognosis of nasopharyngeal carcinoma. However, serum AGR2 levels could not provide advantages in clinical practice for the differential diagnosis of cancer.