Prolyl-4-Hydroxylase α Subunit 2 Promotes Breast Cancer Progression and Metastasis by Regulating Collagen Deposition

BACKGROUND: Increased collagen deposition provides physical and biochemical signals to support tumor growth and invasion during breast cancer development. Therefore, inhibition of collagen synthesis and deposition has been considered a strategy to suppress breast cancer progression. Collagen prolyl-4-hydroxylase α subunit 2 (P4HA2), an enzyme hydroxylating proline residues in -X-Pro-Gly- sequences, is a potential therapeutic target for the disorders associated with increased collagen deposition. However, expression and function of P4HA2 in breast cancer progression are not well investigated. METHODS: Gene co-expression analysis was performed in the published microarray datasets to identify potential regulators of collagen I, III, and IV in human breast cancer tissue. Expression of P4HA2 was silenced by shRNAs, and its activity was inhibited by 1, 4-DPCA, a prolyl-4-hydroxylase inhibitor. Three-dimensional culture assay was used to analyze roles of P4HA2 in regulating malignant phenotypes of breast cancer cells. Reduced deposition of collagen I and IV was detected by Western blotting and immunofluorescence. Control and P4HA2-silenced breast cancer cells were injected into fat pad and tail vein of SCID mice to examine effect of P4HA2 on tumor growth and lung metastasis. RESULTS: Using gene co-expression analysis, we showed that P4HA2 was associated with expression of Col1A1, Col3A1, and Col4A1 during breast cancer development and progression. P4HA2 mRNA levels were significantly upregulated in breast cancer compared to normal mammary tissue. Increased mRNA levels of P4HA2 correlated with poor clinical outcome in breast cancer patients, which is independent of estrogen receptor status. Silencing P4HA2 expression or treatment with the P4HA inhibitor significantly inhibited cell proliferation and suppressed aggressive phenotypes of breast cancer cells in 3D culture, accompanied by reduced deposition of collagen I and IV. We also found that knockdown of P4HA2 inhibited mammary tumor growth and metastasis to lungs in xenograft models. CONCLUSION: These results suggest the critical role of P4HA2 in breast cancer progression and identify P4HA2 as a potential therapeutic target and biomarker for breast cancer progression

Examining the density and diversity of human activity in the built environment: The case of the pearl river delta, China

Rapid urbanization in China has been accompanied by spatial inefficiency in patterns of human activity, of which 'ghost towns' are the most visible result. In this study, we measure the density and diversity of human activity in the built environment and relate this to various explanatory factors. Using the Pearl River Delta (PRD) as an empirical case, our research demonstrates the distribution of human activity by multi-source data and then explores its dynamics within these areas. This empirical study is comprised of two parts. The first part explores location information regarding human activity in urbanized areas and shows density and diversity. Regression models are applied to explore how density and diversity are affected by urban scale, morphology and by a city's administrative level. Results indicate that: 1) cities with smaller populations are more likely to be faced with lower density and diversity, but they derive greater marginal benefits from improving land use efficiency; 2) the compactness of the layout of urban land, an index reflecting the plane shapes of the built environment, is highly correlated with density and diversity in built-up areas; and 3) the administrative importance of a city has a significant and positive impact on the density of human activity, but no obvious influence on its diversity

The Household Responsibility System, Karl Marx’s Theory of Property and Antony M. Honoré’s Concept of Ownership

The Household Responsibility System (HRS) has improved agricultural productivity and promoted economic growth and thus relieved poverty in the rural population of China. However, the prevailing assumptions about its nature are that it was the result of de-collectivization and privatization (or at least semi-privatization) of land and thus an adaptation of capitalism or semi-capitalism. Moreover, the property rights structure of the HRS in China is also often assumed to be ambiguous and insecure. Grasping the principal characteristics of the HRS requires historical analysis of its origin, development and eventual legislation and institutionalization. Marx's theory of property is the key to understanding the institutional change from the Commune System to the HRS. It reveals that the HRS is one kind of “individual property” that Marx envisioned in post-capitalist society. Antony M. Honoré's theoretical framework of ownership is usefully viewed as a development of Marx's theory; within that framework, the HRS emerges as a kind of “split ownership” and its property rights structure can be judged to be well-defined

Membrane associated collagen XIII promotes cancer metastasis and enhances anoikis resistance

Abstract Background: Increased collagen expression and deposition are associated with cancer progression and poor prognosis in breast cancer patients. However, function and regulation of membrane-associated collagen in breast cancer have not been determined. Collagen XIII is a type II transmembrane protein within the collagen superfamily. Experiments in tissue culture and knockout mouse models show that collagen XIII is involved in cell adhesion and differentiation of certain cell types. In the present study, we determined roles of collagen XIII in breast cancer progression and metastasis. Methods: We analyzed the association of collagen XIII expression with breast cancer development and metastasis using published gene expression profiles generated from human breast cancer tissues. Utilizing gain- and loss- of function approaches and 3D culture assays, we investigated roles of collagen XIII in regulating invasive tumor growth. Using the tumorsphere/mammosphere formation assay and the detachment cell culture assay, we determined whether collagen XIII enhances cancer cell stemness and induces anoikis resistance. We also inhibited collagen XIII signaling with β1 integrin function-blocking antibody. Finally, using the lung colonization assay and the orthotopic mammary tumor model, we investigated roles of collagen XIII in regulating breast cancer colonization and metastasis. Cox proportional hazard (log-rank) test, two-sided Student’s t-test (two groups) and one-way ANOVA (three or more groups) analyses were used in this study. Results: Collagen XIII expression is significantly higher in human breast cancer tissue compared with normal mammary gland. Increased collagen XIII mRNA levels in breast cancer tissue correlated with short distant recurrence free survival. We showed that collagen XIII expression promoted invasive tumor growth in 3D culture, enhanced cancer cell stemness, and induced anoikis resistance. Collagen XIII expression induced β1 integrin activation. Blocking β1 integrin activation significantly reduced collagen XIII-induced invasion and mammosphere formation. Importantly, silencing collagen XIII in MDA-MB-231 cells reduced lung colonization and metastasis. Conclusions: Our results demonstrate a novel function of collagen XIII in promoting cancer metastasis, cell invasion, and anoikis resistance