Rab22a Promotes Epithelial-Mesenchymal Transition in Papillary Thyroid Carcinoma by Activating PI3K/AKT/mTOR Signaling Pathway.

Background: Rab22a is a member of the RAS superfamily, involved in early endosome formation and intracellular vesicle transport. Rab22a is significantly upregulated in a variety of malignant tumors. However, its function in thyroid cancer has never been addressed. Methods: The expression of Rab22a in paraffin sections of 101 patients was detected by immunohistochemical staining. By upregulating and downregulating the expression of Rab22a in thyroid cancer cell lines, the effect of Rab22a on cell proliferation, invasion, and migration was analyzed. Co-IP was employed, and the interaction between Rab22a and PI3Kp85α was shown. The function of Rab22a on PI3K/AKT/mTOR signaling and epithelial-mesenchymal transition (EMT) was further studied by western blot analysis. Results: Immunostaining showed that Rab22a was significantly overexpressed in thyroid cancer tissues but negative in adjacent normal tissues or nodular goiters. The proliferation, migration, invasion, and EMT in papillary thyroid carcinoma cell lines were enhanced upon Rab22a overexpression but inhibited after knocking down Rab22a. The co-IP assay demonstrated an interaction between Rab22a and PI3K85α, an effector of PI3K. We further found that Rab22a can activate the PI3K/AKT/mTOR signaling pathway. However, the ability of Rab22a to promote the proliferation, invasion, migration, and EMT of papillary thyroid carcinoma cells was significantly inhibited after being treated with LY294002, a PI3K inhibitor. Conclusions: Rab22a can promote the EMT process and enhance proliferation, migration, and invasion of papillary thyroid carcinoma cells by activating the PI3K/AKT/mTOR signaling pathway. Our study provides new pathological diagnosis clues and clinical treatment targets for thyroid cancer.

Rab22a promotes the proliferation, migration, and invasion of lung adenocarcinoma via up-regulating PI3K/Akt/mTOR signaling pathway.

Rab22a, a member of the proto-oncogene RAS family, belongs to the Rab5 subfamily. It participates in early endosome formation and regulates vesicle trafficking. The relationship between Rab22a and tumorigenesis remains elusive. In non-small cell lung cancer specimens, immunohistochemical staining showed consistently high expression of Rab22a in lung adenocarcinoma, but not in squamous cell carcinoma. In lung adenocarcinoma cell lines, A549 and H1299, transfection with Rab22a significantly promoted cell proliferation, migration, and invasion, whereas interference with Rab22a specific siRNA significantly inhibited the above capacities. Transfection with Rab22a also up-regulated the phosphorylation levels of core effector proteins on the PI3K/Akt/mTOR pathway. The Co-IP assay further confirmed the interaction between Rab22a and PI3Kp85α, the core regulatory subunit of PI3K. Application of rapamycin, the mTOR inhibitor, significantly reduced the upregulation of the proliferation, migration, and invasion abilities of lung adenocarcinoma cells transfected with Rab22a. These results suggest that Rab22a can promote the malignant phenotype of lung adenocarcinoma by upregulating the PI3K/Akt/mTOR signaling pathway, and may function as a potential anti-tumor therapeutic target.

Serglycin induces osteoclastogenesis and promotes tumor growth in giant cell tumor of bone.

Giant cell tumor of bone (GCTB) is an aggressive osteolytic bone tumor characterized by the within-tumor presence of osteoclast-like multinucleated giant cells (MGCs), which are induced by the neoplastic stromal cells and lead to extensive bone destruction. However, the underlying mechanism of the pathological process of osteoclastogenesis in GCTB is poorly understood. Here we show that the proteoglycan Serglycin (SRGN) secreted by neoplastic stromal cells plays a crucial role in the formation of MGCs and tumorigenesis in GCTB. Upregulated SRGN expression and secretion are observed in GCTB tumor cells and patients. Stromal-derived SRGN promotes osteoclast differentiation from monocytes. SRGN knockdown in stromal cells inhibits tumor growth and bone destruction in a patient-derived orthotopic xenograft model of mice. Mechanistically SRGN interacts with CD44 on the cell surface of monocytes and thus activates focal adhesion kinase (FAK), leading to osteoclast differentiation. Importantly, blocking CD44 with a neutralizing antibody reduces the number of MGCs and suppresses tumorigenesis in vivo. Overall, our data reveal a mechanism of MGC induction in GCTB and support CD44-targeting approaches for GCTB treatment.

Diagnosis of NUT Carcinoma Despite False-Negative Next-Generation Sequencing Results: A Case Report and Literature Review.

Nuclear protein in testis (NUT) carcinoma (NC) is a poorly differentiated malignant tumor with a poor prognosis, which is caused by the NUTM1 gene rearrangement. Positive staining of NUT using immunohistochemistry (IHC) or gene rearrangement of NUTM1 revealed by genetic analysis, such as fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS), are important strategies used for accurate diagnosis. In the current study, we present a case of NC in an 18-year-old man who had a chief complaint of nasal congestion, nasal bleeding, and anosmia. Magnetic resonance imaging revealed a mass in the nasal cavity and nasal septum. The initial pathological diagnosis was basaloid squamous cell carcinoma. Based on the tumor location and abrupt keratinization, further genetic tests were performed, and NC was diagnosed using FISH, which was further verified by IHC. However, neither DNA-based NGS nor RNA-based NGS revealed the NUTM1 gene rearrangement. Using this case as a basis, we have reviewed the related literature, compared the common diagnostic methods of NC, and discussed the advantages and limitations of current tools employed for molecular analysis of the gene fusion.

Expression of P-aPKC-iota, E-cadherin, and beta-catenin related to invasion and metastasis in hepatocellular carcinoma.

OBJECTIVES: Atypical protein kinase C iota (aPKC-iota) and its associated intracellular molecules, E-cadherin and beta-catenin, are important for cell polarization in tumorigenesis and progression. Expression of aPKC-iota, P-aPKC-iota (activated aPKC-iota), E-cadherin, and beta-catenin in hepatocellular carcinoma (HCC) was measured, and correlation with clinicopathological characteristics of HCC was analyzed. METHODS: Paraffin-embedded tumor tissue was obtained from patients with HCC after resection without preoperative radiotherapy or chemotherapy. Gene expression was detected by polymerase chain reaction (PCR), and protein expression was detected by immunohistochemistry and Western blot analysis. Expressions of aPKC-iota, P-aPKC-iota, E-cadherin, and beta-catenin were analyzed with relation to the clinicopathological data. RESULTS: The gene and protein expression of aPKC-iota are obviously higher in HCC tissues than that in peritumoral tissues and normal tissues by semiquantitative PCR and immunohistochemistry methods. Accumulation of aPKC-iota in HCC cytoplasm and nucleolus inhibited the later formation of belt-like adherens junctions (AJs) and/or tight junctions (TJs) in cell-cell contact. E-cadherin was reduced and accumulation of cytoplasm beta-catenin was increased in HCC. The expression of aPKC-iota was closely related to pathological differentiation, tumor size, invasion, and metastasis of HCC. CONCLUSION: Accumulation of cytoplasm aPKC-iota may reflect pathological differentiation, invasion, and metastasis potential of HCC. In this regard, our study on HCC revealed the potential usefulness of aPKC-iota, E-cadherin, and beta-catenin as a prognostic marker, closely related to pathological differentiation, invasion, metastasis, and prognosis of HCC.

Significance and expression of atypical protein kinase C-iota in human hepatocellular carcinoma.

BACKGROUND AND OBJECTIVE: Previous studies have indicated that abnormal expression of atypical protein kinase C (aPKC-iota) plays a critical role in occurrence and progression of malignant tumor. This study analyzed the correlation of aPKC-iota with clinicopathology in hepatocarcinoma and Cyclin E and investigated molecular mechanisms of invasion and metastasis of hepatocellular carcinoma. MATERIALS AND METHODS: The expression of the aPKC-iota gene was examined by reverse transcription-polymerase chain reaction in 7 specimens of normal liver tissues and 43 of hepatoma and adjacent tissues. Expression of aPKC-iota and Cyclin E protein was detected using immunohistochemistry and Western blot. Finally, we analyzed the correlation of aPKC-iota with clinicopathologic characteristics and invasion of hepatoma. RESULTS: The expression value (0.844 +/- 0.315) of aPKC-iota gene is obviously higher in hepatoma than the value (0.530 +/- 0.217) in adjacent tissues and the value (0.372 +/- 0.130) in normal tissue (P = 0.009). The positive expression rate (58.1%) of aPKC-iota protein in hepatoma is remarkably higher than the rate (23.3%) of adjacent tissues. The expression of aPKC-iota has a positive correlation with the expression of Cyclin E, differentiation degree, and invasion of tumor (P < 0.05). CONCLUSIONS: Differentiation degree and invasion of hepatoma are related to the expression of aPKC-iota, which plays an important role in invasion and metastasis of hepatoma.

Correlation of aPKC-iota and E-cadherin expression with invasion and prognosis of cholangiocarcinoma.

BACKGROUND: The abnormal expression of atypical protein kinase C-iota (aPKC-iota) subtype and E-cadherin play important roles in tumor occurrence and progression. This study was designed to investigate the correlation of expression of aPKC-iota and E-cadherin with the clinicopathological characteristics and prognosis of cholangiocarcinoma, and to analyze the molecular mechanisms of invasion and metastasis of the tumor. METHODS: EnVision immunohistochemistry was used to detect the expression of aPKC-iota and E-cadherin in 9 specimens of benign bile duct tissues, 35 specimens of cholangiocarcinoma and 6 specimens of metastatic cholangiocarcinoma. The relationship of the expression with clinicopathological characteristics, invasion and prognosis of cholangiocarcinoma was analyzed. A multivariate regression analysis was made of these data by the Cox proportional hazard model. RESULTS: The positive expression level of aPKC-iota in cholangiocarcinoma was remarkably higher than that in benign bile duct tissues (68.6% vs. 11.1%, P=0.006), but the expression level of E-cadherin was lower in cholangiocarcinoma than in benign bile duct tissues (37.1% vs. 88.9%, P=0.016). Correlation analysis revealed that the expression of aPKC-iota was positively related to tumor differentiation and invasion, whereas that of E-cadherin was entirely the contrary. Moreover, there was a negative relationship between the expression of aPKC-iota and that of E-cadherin (r=-0.287, P<0.05). Univariate analysis showed that the overall survival rate of the group with a higher expression of aPKC-iota in cholangiocarcinoma was remarkably lower than that of the group with a lower expression (P<0.01); multivariate analysis revealed that the expressions of aPKC-iota and E-cadherin are important prognostic factors for cholangiocarcinoma (P<0.05). CONCLUSIONS: The expressions of aPKC-iota and E-cadherin may reflect the differentiation and invasive potential of cholangiocarcinoma. aPKC-iota and E-cadherin may be independent prognostic factors and, when used in combination with clinicopathological characteristics, may increase the accuracy in predicting the prognosis of patients with cholangiocarcinoma. As a polar regulative associated protein, aPKC-iota may play an important role in the invasion and metastasis of cholangiocarcinoma.