对铂类/紫杉醇为主的耐药是卵巢癌化疗失败的主要原因，而抑癌基因和细胞自噬异常是耐药调控的重要机制。同属laminin家族的潜在抑癌基因LAMC3和LAMA2与肿瘤进展相关，但与卵巢癌耐药调控的研究极少见。我们研究发现LAMC3和LAMA2在卵巢癌耐药细胞和组织中低表达，且LAMC3低表达与不良预后显著相关。过表达LAMC3能降低卵巢癌耐药细胞的耐药性，并抑制ATG12等自噬蛋白的表达，降低LC3-II/I比值。基于大数据挖掘，LAMC3与LAMA2的表达正相关，LAMC3与ATG12在耐药组织中的表达负相关，且LAMC3和LAMA2都与ATG16L2负相关。由此我们提出科学假设：LAMC3和LAMA2通过负调控细胞自噬影响卵巢癌耐药。本项目将在细胞、动物、分子和临床水平上系统研究LAMC3和LAMA2调节自噬参与耐药的机制，为卵巢癌分子靶向治疗及耐药逆转提供依据，具有重要的理论和应用价值。

Although the platinum and paclitaxel-based chemotherapy, which is the current preferred treatment modality in human ovarian cancer, significantly reduces the mortality rates and prolongs the survival time of patients, the main obstacle to a successful treatment for ovarian cancer is the development of drug resistance to combination chemotherapy. Drug resistance results from a variety of factors including individual variations in patients and somatic cell genetic differences in tumors. However, regardless of mechanisms, abnormality of tumor suppressor expression and autophagy activity clearly contributes to drug resistance in ovarian cancer. The potential tumor suppressor LAMC3 and LAMA2 are the laminin genes and involved in the regulation of cancer progression and development, while their studies on ovarian cancer and drug resistance are rare. We revealed that the expression of LAMC3 and LAMA2 was significantly down-regulated in drug-resistant cells and tissues compared with controls in ovarian cancer. Low expression of LAMC3 in lab-collected 51 specimens and in TCGA cohort of 489 tissues was significantly associated with poor disease-free survival and overall survival. Over-expression of LAMC3 in paclitaxel-resistant SKOV3 and HeyA8 cells could greatly increase the sensitivity of the cells to paclitaxel. Furthermore, over-expression of LAMC3 inhibited the expression of autopahgy proteins such as ATG12, and resulted in a decreased ratio of LC3-II/LC3-I. Consistently, the mRNA expression of LAMC3 and LAMA2 was positively correlated in 489 tissues of TCGA cohort; LAMC3 and ATG12 was negatively correlated in 90 cases of drug resistant tissues, and LAMC3/LAMA2 were both negatively correlated with ATG16L2. Thus, in this application, a scientific hypothesis is proposed that LAMC3 and LAMA2 might be contributed to the modulation of drug resistance by autophagy in ovarian cancer. On the basis of studies on cell model, mouse model and clinical specimens, we aim to systematically illustrate the function and molecular mechanism of these two genes on drug resistance in ovarian cancer by autophagy. The results may pave the way for molecular-targeted therapies, reversal of drug resistance and clinical application in ovarian cancer.